Imidazole, Triazole and tetrazole derivatives

ABSTRACT

Imidazole, triazole and tetrazole derivatives of formula (I) are selective agonists of 5-HT 1  -like receptors and are therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated, wherein the broken circle represents two non-adjacent double bonds in any position in the five-membered ring; two, three or four of V, W, X, Y and Z represent nitrogen and the remainder represent carbon provided that, when two of V, W, X, Y and Z represent nitrogen and the remainder represent carbon, then the said nitrogen atoms are in non-adjacent positions within the five-membered ring; E represents a bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; F represents a group of formula (a); U represents nitrogen or C--R 2  ; B represents oxygen, sulphur or N--R 3  ; R 1  represents a group of formula (i), (ii) or (iii).

This application is a 371 of PCT/GB93/01495 filed 15 Jul. 1993, now WO94/02477 published 3 Feb. 1994.

The present invention relates to a class of substituted imidazole,triazole and tetrazole derivatives which act on 5-hydroxytryptamine(5-HT) receptors, being selective agonists of so-called "5-HT₁ -like"receptors. They are therefore useful in the treatment of clinicalconditions for which a selective agonist of these receptors isindicated.

5-HT₁ -like receptor agonists which exhibit selective vasoconstrictoractivity have recently been described as being of use in the treatmentof migraine (see, for example, A. Doenicke et al., The. Lancet, 1988,Vol. 1, 1309-11). The compounds of the present invention, beingselective 5-HT₁ -like receptor agonists, are accordingly of particularuse in the treatment of migraine and associated conditions, e.g. clusterheadache, chronic paroxysmal hemicrania, headache associated withvascular disorders, tension headache and paediatric migraine.

EP-A-0313397 and WO-A-91/18897 describe separate classes of tryptaminederivatives substituted by various five-membered heteroaliphatic rings,which are stated to be specific to a particular type of "5-HT₁ -like"receptor and thus to be effective therapeutic agents for the treatmentof clinical conditions, particularly migraine, requiring this activity.However, neither EP-A-0313397 nor WO-A-91/18897 discloses or suggeststhe imidazole, triazole and tetrazole derivatives provided by thepresent invention.

EP-A-0497512, published on 5 Aug. 1992, describes a class of substitutedimidazole, triazole and tetrazole derivatives which are stated to beselective agonists of 5-HT₁ -like receptors and hence to be ofparticular use in the treatment of migraine and associated conditions.

The present invention provides a compound of formula I, or a salt orprodrug thereof: ##STR2## wherein the broken circle represents twonon-adjacent double bonds in any position in the five-membered ring;

two, three or four of V, W, X, Y and Z represent nitrogen and theremainder represent carbon provided that, when two of V, W, X, Y and Zrepresent nitrogen and the remainder represent carbon, then the saidnitrogen atoms are in non-adjacent positions within the five-memberedring;

A¹ represents hydrogen, hydrocarbon, a heterocyclic group, halogen,cyano, trifluoromethyl, --OR^(x), --SR^(x), --NR^(x) R^(y), --NR^(x)COR^(y), --NR^(x) CO₂ R^(y), --NR^(x) SO₂ R^(y), or --NR^(z) CTNR^(x)R^(y) ;

A² represents a non-bonded electron pair when four of V, W, X, Y and Zrepresent nitrogen and the other represents carbon; or, when two orthree of V, W, X, Y and Z represent nitrogen and the remainder representcarbon, A² represents hydrogen, hydrocarbon, a heterocyclic group,halogen, cyano, trifluoromethyl, --OR^(x), --SR^(x), --NR^(x) R^(y),--NR^(x) COR^(y), --NR^(x) CO₂ R^(y), --NR^(x) SO₂ R^(y), or --NR^(z)CTNR^(x) R^(y) ;

E represents a bond or a straight or branched alkylene chain containingfrom 1 to 4 carbon atoms;

F represents a group of formula ##STR3##

U represents nitrogen or C--R² ;

B represents oxygen, sulphur or N--R³ ;

R¹ represents a group of formula (i), (ii) or (iii): ##STR4## in which

M represents the residue of an azetidine, pyrrolidine or piperidinering;

p is zero or 1 and q is an integer from 1 to 4,

R², R³, R⁴, R⁵ and R⁶ independently represent hydrogen or C₁₋₆ alkyl;

R^(x) and R^(y) independently represent hydrogen, hydrocarbon or aheterocyclic group, or R^(x) and R^(y) together represent a C₂₋₆alkylene group;

R^(z) represents hydrogen, hydrocarbon or a heterocyclic group;

T represents oxygen, sulphur or a group of formula ═N.G; and

G represents hydrocarbon, a heterocyclic group or anelectron-withdrawing group.

The present invention also provides compounds of formula I above whereinR¹ represents a group of formula (i) or (ii), and the remainingsubstituents are as defined above.

For use in medicine, the salts of the compounds of formula I will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable non-toxic acid such as hydrochloric acid,sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid,benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g. sodium or potassium salts; alkalineearth metal salts, e.g. calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g. quaternary ammonium salts.

The term "hydrocarbon" as used herein includes straight-chained,branched and cyclic groups containing up to 18 carbon atoms, suitably upto 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitablehydrocarbon groups include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl and aryl(C₁₋₆)alkyl.

The expression "a heterocyclic group" as used herein includes cyclicgroups containing up to 18 carbon atoms and at least one heteroatompreferably selected from oxygen, nitrogen and sulphur. The heterocyclicgroup suitably contains up to 15 carbon atoms and conveniently up to 12carbon atoms, and is preferably linked through carbon. Examples ofsuitable heterocyclic groups include C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl and heteroaryl(C₁₋₆)alkylgroups.

Suitable alkyl groups include straight-chained and branched alkyl groupscontaining from 1 to 6 carbon atoms. Typical examples include methyl andethyl groups, and straight-chained or branched propyl and butyl groups.Particular alkyl groups are methyl, ethyl and t-butyl.

Suitable alkenyl groups include straight-chained and branched alkenylgroups containing from 2 to 6 carbon atoms. Typical examples includevinyl and allyl groups.

Suitable alkynyl groups include straight-chained and branched alkynylgroups containing from 2 to 6 carbon atoms. Typical examples includeethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbonatoms. Particular cycloalkyl groups are cyolopropyl and cyclohexyl.

A particular aryl group is phenyl.

Particular aryl(C₁₋₆)alkyl groups include benzyl, phenethyl andphenylpropyl,

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidyl,piperidyl, piperazinyl and morpholinyl groups.

Suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl andthiadiazolyl groups.

Particular heteroaryl(C₁₋₆)alkyl groups include pyridylmethyl andpyrazinylmethyl.

The hydrocarbon and heterocyclic groups may in turn be optionallysubstituted by one or more groups selected from C₁₋₆ alkyl, adamantyl,phenyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ aminoalkyl, trifluoromethyl,hydroxy, C₁₋₆ alkoxy, aryloxy, keto, C₁₋₃ alkylenedioxy, nitro, cyano,carboxy, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkylcarbonyloxy, arylcarbonyloxy, C₂₋₆ alkylcarbonyl, arylcarbonyl,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, arylsulphonyl,NR^(v) R^(w), --NR^(v) COR^(w), --NR^(v) CO₂ R^(w), --NR^(v) SO₂ R^(w),--CH₂ NR^(v) SO₂ R^(w), --NHCONR^(v) R^(w), --CONR^(v) R^(w), --SO₂NR^(v) R^(w) and --CH₂ SO₂ NR^(v) R^(w), in which R^(v) and R^(w)independently represent hydrogen, C₁₋₆ alkyl, aryl or aryl(C₁₋₆)alkyl,or R^(v) and R^(w) together represent a C₂₋₆ alkylene group.

When R^(x) and R^(y), or R^(v) and R^(w), together represent a C₂₋₆alkylene group, this group may be an ethylene, propylene, butylene,pentamethylene or hexamethylene group, preferably butylene orpentamethylene.

When the group G represents an electron-withdrawing group, this group issuitably cyano, nitro, --COR^(x), --CO₂ R^(x) or --SO₂ R^(x), in whichis as defined above.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. In addition,the compounds of formula I above wherein R¹ represents a group offormula (iii) may exist as discrete isomers in which the --NR⁵ R⁶ groupis either cis or trans to the other substituent on the cyclobutane ring.It is to be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

It will be appreciated that the imidazole, triazole and tetrazole ringsof formula I can exist in a variety of isomeric forms having differingsubstitution patterns. These may suitably be represented by formulae IAto IT as follows: ##STR5## wherein A¹, A², E and F are as defined above.Preferred imidazole, triazole and tetrazole rings of formula I includethe rings represented by formulae IA, IC, IG, IH, IK, IL, IM, IN, IP andIQ above, especially IH or IK.

The alkylene chain E may be, for example, 2-methylpropylene.Alternatively, the group E may represent a single bond such that thegroup F in formula I is attached directly to the five-memberedheteroaromatic ring.

The group F is suitably an indole, benzofuran or benzthiophene moiety offormula FA, or an indazole moiety of formula FB: ##STR6## wherein B, R¹,R² and R³ are as defined above; Preferably, the group F represents anindole moiety of structure FC: ##STR7## wherein R¹, R² and R³ are asdefined above, in particular wherein R² and R³ are both hydrogen.

It will be appreciated that when four of V, W, X, Y and Z representnitrogen and the other represents carbon, i.e. when the ring of formulaI is a tetrazole ring, then the group A² will be a non-bonded electronpair. Otherwise, A¹ and A² will independently represent cyano,trifluoromethyl, --OR^(x), --SR^(x), --NR^(x) R^(y), --NR^(x) COR^(y),--NR^(x) CO₂ R^(y), --NR^(x) SO₂ R^(y), or --NR^(z) CTNR^(x) R^(y).

Suitable values for the groups A¹ and/or A² include C₁₋₆ alkyl, C₃₋₇cycloalkyl, aryl, aryl (C₁₋₆) alkyl, C₃₋₇ heterocycloalkyl, heteroaryl,heteroaryl(C₁₋₆)alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylthio, any of whichgroups may be optionally substituted; and hydrogen, halogen, cyano,trifluoromethyl or --NR^(x) R^(y), in which R^(x) and R^(y) are asdefined above. Examples of optional substituents on the groups A¹ and/orA² suitably include trifluoromethyl, C₁₋₆ alkoxy, C₂₋₆ alkoxycarbonyl,C₂₋₆ alkylcarbonyl, C₁₋₆ alkylsulphonyl, arylsulphonyl, amino, mono- ordi(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, arylcarbonylamino, C₂₋₆alkoxycarbonylamino, C₁₋₆ alkylsulphonylamino, arylsulphonylamino, C₁₋₆alkylsulphonylaminomethyl, aminocarbonylamino, mono- ordi(C₁₋₆)alkylaminocarbonylamino, mono- or diarylaminocarbonylamino,pyrrolidylcarbonylamino, aminocarbonyl, mono- ordi(C₁₋₆)alkylaminocarbonyl, C₁₋₆ alkylaminosulphonyl,aminosulphonylmethyl, and mono- or di(C₁₋₆)alkylaminosulphonylmethyl.

Particular values of A¹ and/or A² include hydrogen, methyl,methoxymethyl, aminomethyl, dimethylaminomethyl, acetylaminomethyl,benzoylaminomethyl, t-butoxycarbonylaminomethyl,methylsulphonylaminomethyl, phenylsulphonylaminomethyl,aminocarbonylmethyl, ethyl, aminoethyl, acetylaminoethyl,benzoylaminoethyl, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyi,t-butoxycarbonylaminoethyl, methylsulphonylaminoethyl,aminocarbonylaminoethyl, methylaminocarbonylaminoethyl,t-butylaminocarbonylaminoethyl, phenylaminocarbonylaminoethyl,pyrrolidylcarbonylaminoethyl, cyclopropyl, phenyl,methylsulphonylaminophenyl, aminocarbonylphenyl,methylaminocarbonylphenyl, methylsulphonylaminomethylphenyl,aminosulphonylmethylphenyl, methylaminosulphonylmethylphenyl,dimethylaminosulphonylmethylphenyl, benzyl, trifluoromethylbenzyl,methoxybenzyl, acetylaminobenzyl, methylsulphonylaminobenzyl,aminocarbonylaminobenzyl, aminocarbonylbenzyl,methylaminocarbonylbenzyl, methylsulphonylbenzyl,methylaminosulphonylbenzyl, pyridylmethyl, methoxypyridylmethyl, amino,methylamino, benzylamino, dimethylamino, t-butoxycarbonylaminoethylaminoand methylsulphonylaminoethylamino.

Preferred values of A¹ and/or A² include hydrogen, methyl, ethyl andamino.

When R¹ represents a group of formula (ii), the resulting group is anazetidin-2-ylmethyl, azetidin-3-ylmethyl, pyrrolidin-2-ylmethyl,pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl or piperidin-3-ylmethylgroup, in particular an azetidin-3-ylmethyl or pyrrolidin-2-ylmethylgroup, substituted on the ring nitrogen atom by the group R⁴.

In a particular embodiment, R¹ represents a group of formula (i) inwhich M represents the residue of an azetidine or pyrrolidine ring.Thus, R¹ suitably represents the azetidin-1-ylethyl orpyrrolidin-1-ylethyl moiety.

Preferred values for the groups R², R³, R⁴, R⁵ and R⁶ include hydrogenand methyl.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula II, and salts and prodrugsthereof: ##STR8## wherein

Y¹ represents nitrogen or A¹² --C;

Z¹ represents nitrogen or CH;

n is zero, 1, 2 or 3;

B¹ represents oxygen, sulphur or N--R¹³ ;

A¹¹ and A¹² independently represent C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,heteroaryl, heteroaryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylamino or di(C₁₋₆)alkylamino, any of which groups may be optionallysubstituted; or hydrogen, halogen, cyano, trifluoromethyl or amino;

R¹¹ represents a group of formula (iv), (v) , (vi), (vii) or (viii):##STR9##

and R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ independently represent hydrogen or C₁₋₆alkyl.

Examples of optional substituents on the groups A¹¹ and A¹² suitablyinclude trifluoromethyl, C₁₋₆ alkoxy, C₂₋₆ alkoxycarbonyl, C₂₋₆alkylcarbonyl, C₁₋₆ alkylsulphonyl, arylsulphonyl, amino, mono- ordi(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, arylcarbonylamino, C₂₋₆alkoxycarbonylamino, C₁₋₆ alkylsulphonylamino, arylsulphonylamino, C₁₋₆alkylsulphonylaminomethyl, aminocarbonylamino, mono- ordi(C₁₋₆)alkylamino-carbonylamino, mono- or diarylaminocarbonylamino,pyrrolidylcarbonylamino, aminocarbonyl, mono- ordi(C₁₋₆)alkylaminocarbonyl, C₁₋₆ alkylaminosulphonyl,aminosulphonylmethyl, and mono- or di(C₁₋₆)alkyl-aminosulphonylmethyl.

Particular values of A¹¹ and A¹² with respect to formula II includehydrogen, methyl, ethyl and amino, especially hydrogen.

Preferably, R¹² and R¹³ each represents hydrogen. Preferably, R¹⁴ ismethyl.

Suitably, R¹⁵ and R¹⁶ are independently selected from hydrogen andmethyl. Preferably, R¹⁵ and R¹⁶ are both methyl.

Specific compounds within the scope of the present invention include:

N-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylazetidine;

N-2-[5-(1,2,4-triazol-1-yl)-1H-indol-3-yl]ethylazetidine;

N-methyl-3-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylazetidine;

N-methyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylpyrrolidine;

(2R)-N-methyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine;

3-[cis-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-1H-indole;

3-[trans-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-1H-indole;

N-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethylazetidine;

N-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3yl]ethylpyrrolidine;

and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

In the treatment of migraine, a suitable dosage level is about 0.01 to250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of i to 4 times per day.

The 1,2,4-triazole compounds of this invention may be prepared by aprocess which comprises reacting a reactive derivative of a carboxylicacid of formula R^(a) --CO₂ H with a compound either of formula III orof formula IV, or a salt thereof: ##STR10## wherein one of R^(a), R^(b)and R^(c) is a group of formula A¹ , another is a group of formula A²and the third is a group of formula --E--F, as defined with reference toformula I above.

Suitable reactive derivatives of the acid R^(a) --CO₂ H include esters,for example C₁₋₄ alkyl esters; thioesters, for examplepyridylthioesters; acid anhydrides, for example (R^(a) --CO)₂ O; acidhalides, for example acid chlorides; orthoesters; and primary, secondaryand tertiary amides.

A preferred reactive derivative of the acid R^(a) --CO₂ H is theiminoether derivative of formula V: ##STR11## where R is C₁₋₄ alkyl.

The reagent of formula III may be generated in situ in the reactionmixture. For example, the reaction may be effected by treating acompound of formula V above with an alkyl hydrazine, e.g. methylhydrazine, followed by a suitable carboxylic acid such as formic acid.

The reaction is conveniently carried out by heating the reagentstogether, optionally in a solvent, for example tetrahydrofuran,dimethylformamide or a lower alkanol such as ethanol, propanol orisopropanol, at about 20° C. to 100° C. for about 1 to 6 hours.

Where R^(a) is a group of formula --E--F and the group F is an indolemoiety of structure FC as defined above, the reactive derivative of acarboxylic acid of formula HO₂ C--E--F may be prepared by reacting acompound of formula VI: ##STR12## wherein Q represents a reactivecarboxylate moiety, and E is as defined above; with a compound offormula VII or a carbonyl-protected form thereof: ##STR13## wherein R²is as defined above and R²¹ corresponds to the group R¹ as defined aboveor represents a protected derivative thereof; followed by removal of anyprotecting groups present; and subsequently, where required,N-alkylation by standard methods to introduce the moieties R³ and/or R⁴.

Suitable carbonyl-protected forms of the compounds of formula VIIinclude the dimethyl acetal or ketal derivatives.

The reaction of compounds VI and VII may be carried out in a single step(Fischer indole synthesis) or by an initial non-cyclising step at alower temperature to give a compound of formula VIII: ##STR14## whereinQ, E, R² and R²¹ are as defined above; followed by cyclisation using asuitable reagent, such as a polyphosphate ester, to give a compound offormula Q--E--F.

The hydrazines of formula VI may be prepared from the correspondinganilines of formula IX: ##STR15## wherein Q and E are as defined above;by diazotisation followed by reduction. Diazotisation is typicallycarried out using sodium nitrite/conc. HCl and the resulting diazoproduct reduced in situ using, for example, tin(II) chloride/conc. HCl,sodium sulphite/conc. HCl, or sodium sulphite/conc. H₂ SO₄.

The anilines of formula IX may be prepared by reduction of thecorresponding nitro compounds of formula X: ##STR16## wherein Q and Eare as defined above; typically by transfer hydrogenation using ahydrogenation catalyst such as palladium on charcoal in the presence ofa hydrogen donor such as ammonium formate, or alternatively byconventional catalytic hydrogenation or using tin(II) chloride.

Where they are not commercially available, the nitro compounds offormula X may be synthesized by standard methods well known to thoseskilled in the art.

Where R^(a) is a group of formula --E--F and the group F is an indazolemoiety of structure FB as defined above, the reactive derivative of acarboxylic acid of formula HO₂ C--E--F may be prepared by thecyclisation of a compound of formula XI: ##STR17## wherein Q, E and R²¹are as defined above and D² represents a readily displaceable group;followed by removal of any protecting groups present; and subsequently,where required, N-alkylation by standard methods to introduce themoieties R³ and/or R⁴.

The cyclisation of compound XI is conveniently achieved in a suitableorganic solvent at an elevated temperature, for example in a mixture ofm-xylene and 2,6-lutidine at a temperature in the region of 140° C.

The readily displaceable group D² in the compounds of formula XIsuitably represents a C₁₋₄ alkanoyloxy group, preferably acetoxy. WhereD² in the desired compound of formula XI represents acetoxy, thiscompound may be conveniently prepared by treating a carbonyl compound offormula XII: ##STR18## wherein Q, E and R²¹ are as defined above; or aprotected derivative thereof; with hydroxylamine hydrochloride,advantageously in pyridine at the reflux temperature of the solvent;followed by acetylation with acetic anhydride, advantageously in thepresence of a catalytic quantity of 4-dimethylaminopyridine, indichloromethane at room temperature.

The N-formyl protected derivative of the intermediate of formula XII maybe conveniently prepared by ozonolysis of an indole derivative offormula XIII: ##STR19## wherein Q, E and R²¹ are as defined above;followed by a reductive work-up, advantageously using dimethylsulphide.

The indole derivative of formula XIII may be prepared by methodsanalogous to those described in the accompanying Examples, or byprocedures well known from the art.

In an alternative process, the triazole compounds according to theinvention may be prepared by a method which comprises reacting acompound of formula XIV: ##STR20## wherein A¹, E and F are as definedabove, Hal represents halogen, and two of V^(a), W^(a), X^(a), Y^(a) andZ^(a), to one of which the group Hal is attached, represent carbon andthe remainder represent nitrogen; with a reagent which provides an anion⁻ A², where A² is as previously defined.

Reagents which may provide the anion ⁻ A² include Grignard reagents A²MgHal (where Hal=halogen); organocuprate reagents such as LiA² ₂ Cu;organolithium reagents A² Li; or compounds which stabilise the anion bymeans of an adjacent activating group such as an ester or enolisableketone function. In this case, the adjacent ester or ketone function maybe retained after the process is complete, or may be removed. Forexample, an ester moiety may be hydrolysed and decarboxylated.

The 1,2,3-triazole compounds according to the present invention may beprepared by a process which comprises the cycloaddition of an alkyne offormula R^(a) --C.tbd.C--R^(b) with an azide of formula R^(c) --N₃,where R^(a) R^(b) and R^(c) are as defined above.

The cycloaddition reaction may be conveniently effected in a suitablesolvent such as tetrahydrofuran, ideally by heating in an autoclave for8 hours.

The tetrazole compounds in accordance with the invention may be preparedby a process which comprises the cycloaddition of a nitrile of formulaN.tbd.C--R^(d) with an azide of formula R^(e) --N₃, where one of R^(d)and R^(e) represents a group of formula A¹ and the other is a group offormula --E--F, as defined previously.

The cycloaddition reaction is conveniently effected by heating thereactants together at an elevated temperature, e.g. a temperature in theregion of 150° C., in a suitable solvent such as N-methylpyrrolid-2-one,advantageously in the presence of triethylamine hydrochloride. Theproduct obtained from the cycloaddition reaction will generally be amixture of isomers substituted by the A¹ group at positions 1 and 2 ofthe tetrazole ring, corresponding to structures IL and IM respectivelyas defined above. These isomers may conveniently be separated usingconventional techniques such as chromatography.

In an alternative process, the tetrazole compounds of the invention maybe prepared by a method which comprises reacting a compound of formulaR^(e) --L with a tetrazole derivative of formula XV: ##STR21## whereinone of R^(d) and R^(e) represents a group of formula A¹ and the other isa group of formula --E--F, as defined above, and L represents a suitableleaving group; in the presence of a base such as triethylamine.

The leaving group L suitably represents halogen, e.g. bromine or iodine,or a sulphonate derivative such as tosylate or mesylate.

The reaction is conveniently carried out in a suitable organic solvent,e.g. acetonitrile, at room temperature.

The tetrazole derivatives of formula XV may be prepared by cycloadditionof a nitrile of formula N.tbd.C--R^(d) with sodium azide, advantageouslyunder the conditions described above for the reaction between thenitrile N.tbd.C--R^(d) and the azide R^(e) --N₃ ; followed byacidification with a mineral acid such as hydrochloric acid.

In a further process, the compounds according to the invention whereinthe group F is an indole moiety of structure FC as defined above may beprepared by a method which comprises reacting a compound of formula XVI:##STR22## wherein V, W, X, Y, Z, A¹, A² and E are as defined above; witha compound of formula VII as defined above, or a carbonyl-protected formthereof, e.g. the dimethyl acetal or ketal; followed by removal of anyprotecting groups present; and subsequently, where required,N-alkylation by standard methods to introduce the moieties R³ and/or R⁴.

As with that between compounds VI and VII, the reaction betweencompounds XVI and VII may be carried out in a single step (Fischerindole synthesis) or by an initial non-cyclising step at a lowertemperature to give a compound of formula XVII: ##STR23## wherein V, W,X, Y, Z, A¹, A², E, R² and R²¹ are as defined above; followed bycyclisation using a suitable reagent, e.g. a polyphosphate ester.

The hydrazines of formula XVI may be prepared from the correspondinganilines of formula XVIII: ##STR24## wherein V, W, X, Y, Z, A¹, A² and Eare as defined above; by methods analogous to those described above withreference to the compounds of formula IX.

The anilines of formula XVIII may be prepared from the correspondingnitro compounds of formula XIX: ##STR25## wherein V, W, X, Y, Z, A¹, A²and E are as defined above; by methods analogous to those describedabove with reference to the compounds of formula X.

The nitro compounds of formula XIX may be prepared by a variety ofmethods which will be readily apparent to those skilled in the art. Forexample, where V represents a nitrogen atom, the relevant compounds offormula XIX may be prepared by reacting the anion of a compound offormula XX with a compound of formula XXI: ##STR26## wherein W, X, Y, Z,A¹, A² and E are as defined above, and D³ represents a readilydisplaceable group.

Where compound XX is a triazole or tetrazole derivative, the anionthereof may be generated by carrying out the reaction in a base such astriethylamine. Where compound XX is an imidazole derivative, the anionthereof may conveniently be generated if the reaction is carried out inthe presence of sodium hydride using N,N-dimethylformamide as solvent.Where salts of the compounds of formula XX are commercially available,e.g. the sodium salt of 1,2,4-triazole, these are advantageouslyutilised in N,N-dimethylformamide solution in place of the compounds offormula XX themselves, with no requirement in this instance foradditional base to be present in the reaction mixture.

The readily displaceable group D³ in the compounds of formula XXI issuitably a halogen atom, preferably bromine; except when the moiety D³is attached directly to the aromatic ring, i.e. when E represents abond, in which case D³ is preferably fluorine.

In an alternative approach, the compounds of formula XIX wherein thefive-membered heteroaromatic ring is a 1,2,4-triazol-1-yl moiety and A¹and A² are both hydrogen may be prepared by reacting4-amino-1,2,4-triazole with a compound of formula XXI as defined above,followed by deamination of the resulting 1-substituted4-amino-4H-1,2,4-triazolium salt by treatment with nitrous acid andsubsequent neutralisation. This transformation, which may beaccomplished in two separate steps or advantageously as a "one-pot"procedure with both steps combined, is conveniently effected usingreaction conditions analogous to those described in J. Org. Chem., 1989,54, 731.

Where they are not commercially available, the nitro compounds offormula XXI above may be prepared by procedures analogousto thosedescribed in the accompanying Examples, or by methods well known fromthe art.

In an alternative approach to the. 1,2,4-triazole derivatives, the nitrocompounds of formula XIX may be prepared from those of formula X aboveby appropriate modification of the moiety Q using, for example, methodsanalogous to those described above with reference to the compounds offormulae III and IV. Thus, for example, since Q in the compounds offormula X represents a reactive carboxylate moiety, the compounds offormula XIX may be prepared therefrom by reaction with a compound offormula A² --C(═NNHA¹)NH₂ or A² --C(═NNH₂)NHA¹.

Following a further representative pathway, the aniline derivatives offormula XVIII wherein the five-membered heteroaromatic ring is a1,2,4-triazol-4-yl moiety, E is a bond and A¹ and A² are both hydrogenmay be prepared by reacting the hydrazine derivative of formula XXIIwith the acetanilide of formula XXIII: ##STR27## followed by removal ofthe N-acetyl protecting group.

The reaction between compounds XXII and XXIII is conveniently effectedin refluxing toluene, advantageously in the presence of a catalyticquantity of p-toluenesulphonic acid. Subsequent removal of the N-acetylprotecting group is typically effected in hot aqueous 5N hydrochloricacid.

The hydrazine derivative of formula XXII can be prepared fromN,N'-diformylhydrazine by reaction with thionylchloride/N,N-dimethylformamide, as reported in J. Chem. Soc. (C), 1967,1664, and subsequent treatment with sodium methoxide in methanol.

The acetanilide of formula XXIII may be prepared by reduction of thecorresponding nitro compound of formula XXIV: ##STR28## typically bytransfer hydrogenation using a hydrogenation catalyst in the presence ofa hydrogen donor such as ammonium formate, or alternatively byconventional catalytic hydrogenation or using tin(II) chloride.

The nitro compound of formula XXIV is commercially available from theAldrich Chemical Company Ltd., Gillingham, United Kingdom.

In a still further process, the compounds according to the inventionwherein the group F is an indazole moiety of structure FB as definedabove may be prepared by a method which comprises cyclising a compoundof formula XXV: ##STR29## wherein V, W, X, Y, Z, A¹, A², E, R²¹ and D²are as defined above; followed by removal of any protecting groupspresent; and subsequently, where required, N-alkylation by standardmethods to introduce the moieties R³ and/or R⁴.

As with the cyclisation of compound XI, that of compound XXV isconveniently achieved in a suitable organic solvent at an elevatedtemperature, for example in a mixture of m-xylene and 2,6-lutidine at atemperature in the region of 140° C.

The compounds of formula XXV may, for example, be prepared from thecorresponding compound of formula XXVI: ##STR30## wherein V, W, X, Y, Z,A¹, A², E and R²¹ are as defined above; or a protected derivativethereof; which in turn may be prepared from the corresponding compoundof formula XXVII: ##STR31## wherein V, W, X, Y, Z, A¹, A², E and R²¹ areas defined above; using methods analogous to those described above withreference to the compounds of formulae XII and XIII. Thus, for example,since Q in the compounds of formula XIII represents a reactivecarboxylate moiety, the 1,2,4-triazole derivatives of formula XXVII maybe prepared therefrom by reaction with a compound of formula A²--C(═NNHA¹)NH₂ or A² --C(═NNH₂)NHA¹.

In a yet further process, the compounds according to the inventionwherein the group F is a benzofuran or benzthiophene moiety may beprepared by a method which comprises cyclising a compound of formulaXXVIII: ##STR32## wherein V, W, X, Y, Z, A¹, A², E, R² and R²¹ are asdefined above, and B^(a) represents oxygen or sulphur; followed byremoval of any protecting groups present; and subsequently, whererequired, N-alkylation by standard methods to introduce the moiety R⁴.

The cyclisation is conveniently effected by using polyphosphoric acid ora polyphosphate ester, advantageously at an elevated temperature.

The compounds of formula XXVIII may be prepared by reacting a compoundof formula XXIX with a compound of formula XXX: ##STR33## wherein V, W,X, Y, Z, A¹, A², E, B^(a), R² and R²¹ are as defined above, and Halrepresents halogen.

The reaction is conveniently effected in the presence of a base such assodium hydroxide.

The hydroxy and mercapto derivatives of formula XXIX may be prepared bya variety of methods which will be readily apparent to those skilled inthe art. In one such method, the anion of a compound of formula XX asdefined above is reacted with a compound of formula XXXI: ##STR34##wherein D³, E and B^(a) are as defined above; to afford an intermediateof formula XXIX wherein V is nitrogen.

The compounds of formula XXX and XXXI, where they are not commerciallyavailable, may be prepared by standard procedures well known in the art.

The intermediates of formula VII wherein R²¹ represents a group offormula (i) as defined above with reference to R¹, or thecarbonyl-protected forms thereof, may conveniently be prepared byreacting a compound of formula XXXII, or a carbonyl-protected formthereof, with a compound of formula XXXIII: ##STR35## wherein R² and Mare as defined above; and Hal represents halogen, especially chlorine.The reaction is suitably carried out in the presence of a base such aspotassium carbonate, typically in a solvent such asN,N-dimethylformamide.

The preparation of a typical intermediate of formula VII, wherein R²¹represents an azetidin-3-ylmethyl moiety protected on the ring nitrogenatom by a t-butoxycarbonyl (BOC) group, is illustrated by the followingreaction scheme: ##STR36##

The starting compound XXXIV is known from J. Chem. Soc., Chem Commun.,1968, 93. Step 1 of the reaction scheme comprises oxidation of thehydroxy group of compound XXXI to a carbonyl group using pyridine.SO₃ indimethyl sulphoxide (DMSO) and triethylamine; followed by reaction ofthe resulting azetidinone derivative with the Horner-Emmons reagent MeO₂C.CH₂.PO(OEt)₂ in the presence of sodium hydride, using tetrahydrofuran(THF) as the solvent. In Step 2, the double bond of the azetidine olefinester is hydrogenated over palladium-charcoal in methanol; the methylester group is then reduced to hydroxymethyl by treatment with lithiumaluminium hydride in THF; and the diphenylmethyl protecting group is inturn removed by treatment with palladium hydroxide on charcoal, withmethanol serving as the solvent. Step 3 involves protection of theazetidine nitrogen as the N-t-butoxycarbonyl (N-BOC) carbamatederivative; followed by conversion of the primary hydroxy group totosyloxy by reaction with p-toluenesulphonyl chloride (tosyl chloride,TsCl) in pyridine/dichloromethane. Displacement of the tosyloxy group bycyanide ion in Step 4 is followed in Step 5 by reduction of theresulting cyano compound to the corresponding aldehyde derivative usingdiisobutylaluminium hydride (DIBAL-H) in THF, with an ammonium chloridework-up.

The preparation of a further typical intermediate of formula VII, inwhich R²¹ represents a pyrrolidin-2-ylmethyl moiety protected on thering nitrogen atom by a BOC group, is illustrated by the followingreaction scheme: ##STR37##

The starting compound XXXV is commercially available from AldrichChemical Company Ltd., Gillingham, U.K. Step 1 of the reaction schemeinvolves protection of the pyrrole nitrogen as the N-t-butoxycarbonyl(N-BOC) carbamate derivative; followed by reaction of the formyl moietyin the 2-position with the Horner-Emmons reagent MeO₂ C.CH₂.PO(OEt)₂ inthe presence of sodium hydride, using THF as the solvent. In Step 2, thepyrrole and exocyclic double bonds are hydrogenated over platinum oxidein acetic acid. This is followed in Step 3 by partial reduction of theside-chain methyl ester group to an aldehyde moiety using DIBAL-H in THFat -80° C.

In a variant of the reaction scheme described immediately above, achiral intermediate of formula VII, in which R²¹ represents apyrrolidin-2-ylmethyl moiety having a chiral centre at the 2-positionand protected on the ring nitrogen atom by a BOC group, is illustratedby the following reaction scheme: ##STR38##

The starting compound XXXVI, D-prolinol, is commercially available fromAldrich Chemical Company Ltd., Gillingham, U.K. Step 1 of the reactionscheme involves protection of the pyrrolidine nitrogen as the N-BOCderivative, typically using BOC anhydride in dichloromethane; followedby Swern oxidation (oxalyl chloride/dimethylsulphoxide/dichloromethane/-78° C., then triethylamine) of the terminalhydroxy group to an aldehyde moiety. Step 2 involves reaction with theHorner-Emmons reagent MeO₂ C.CH₂.PO(OEt)₂ in the presence of sodiumhydride, using THF as the solvent. In Step 3 the side-chain double bondis reduced, conveniently by catalytic hydrogenation overpalladium-charcoal in aqueous methanol; and the methyl ester moiety isthen partially reduced to an aldehyde functionality using DIBAL-H in THFat -78° C., to give the desired product of formula XXXVII.

As will be appreciated, the compound corresponding to compound XXXVII,but having the opposite stereochemistry at the 2-position of thepyrrolidine ring, is readily obtainable, using an identical sequence ofsteps, from L-prolinol (i.e. the opposite antipode of compound XXXVI),which is also commercially available from Aldrich Chemical Company Ltd.

The preparation of a still further typical intermediate of formula VII,in which R²¹ represents a BOC-protected 3-aminocyclobutan-1-yl moiety,is illustrated by the following reaction scheme: ##STR39##

The starting compound XXXVIII is known from Coll. Czech. Chem. Commun.,1981, 47, 2440. Step 1 of the reaction scheme involves treatment thereofwith diphenylphosphoryl azide and 2-methyl-2-propanol in the presence oftriethylamine under reflux, to convert the carboxylic acid moiety intoan --NHBOC group; followed by removal of the O-benzyl protecting groupby catalytic hydrogenation over palladium/carbon. In Step 2, the hydroxygroup is oxidised to keto using pyridinium chlorochromate, orN-methylmorpholine N-oxide in the presence oftetrapropylammoniumperruthenate and molecular sieve; and the resultingketo group is in turn reacted with the Horner-Emmons reagent MeO₂C.CH₂.PO(OEt)₂ in the presence of potassium bis(trimethylsilyl)amide.Step 3 comprises reduction of the exocyclic double bond, conveniently bycatalytic hydrogenation over palladium on carbon; and then partialreduction of the side-chain methyl ester group to an aldehyde moietyusing DIBAL-H in toluene at about -80° C.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art. Indeed, as will be appreciated, the compound of formula XVabove in which R^(d) is a group of formula --E--F is itself a compoundof formula I in which A¹ is hydrogen and A² represents a non-bondedelectron pair. In particular, a compound of formula I wherein R³ ishydrogen initially obtained may be converted into a compound of formulaI wherein R³ represents C₁₋₆ alkyl by standard alkylation techniques,for example by treatment with an alkyl iodide, e.g. methyl iodide,typically under basic conditions, e.g. sodium hydride indimethylformamide, or triethylamine in acetonitrile. Similarly, acompound of formula I wherein R⁴, R⁵ or R⁶ represents hydrogen initiallyobtained may be converted into a compound of formula I wherein R⁴, R⁵ orR⁶ is other than hydrogen, for example by conventional N-alkylationtechniques, e.g. by treatment with the appropriate aldehyde in thepresence of a reducing agent such as sodium cyanoborohydride.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. The novel compounds may, for example, be resolved into theircomponent enantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (-)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The novel compounds may also beresolved by formation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The ability of test compounds to bind to 5-HT₁ -like receptors wasmeasured in membranes prepared from pig caudate using the proceduredescribed in J. Neurosci., 1987, 7, 894. Binding was determined using 2nM 5-hydroxytryptamine creatinine sulphate, 5-[1,2-³ H(N)] as aradioligand. Cyanopindolol (100 nM) and mesulergine (100 nM) wereincluded in the assay to block out 5-HT_(1A) and 5-HT_(1C) binding sitesrespectively. The concentration of the compounds of the accompanyingExamples required to displace 50% of the specific binding (IC₅₀) isbelow 1 μM in each case.

The activity of test compounds as agonists of the 5-HT₁ -like receptorwas measured in terms of their ability to mediate contraction of thesaphenous vein of New Zealand White rabbits, using the proceduredescribed in Arch. Pharm., 1990, 342, 111. Agonist potencies werecalculated as --log₁₀ EC₅₀ (pEC₅₀) values, from plots of percentage 5-HT(1 μM) response against the concentration of the agonist. The compoundsof the accompanying Examples were found to possess pEC₅₀ values in thisassay of not less than 5.0 in each case.

EXAMPLE 1

N-2-[5-(1,2,4-Triazol-1-ylmethyl)-1H-indol-3-yl]ethyl azetidine.Hydrogen Oxalate.

INTERMEDIATE 1

4-(1-Azetidinyl)butanal dimethylacetal

A mixture of azetidine (2.0 g, 35.0 mmol), 4-chlorobutanaldimethylacetal (5.88 g, 39.0 mmol) and K₂ CO₃ (5.38 g, 39.0 mmol), inanhydrous DMF (100ml), was stirred at room temperature for 72 h. Water(50 ml) was added and the mixture extracted with EtOAc (3×150 ml). Thecombined extracts were washed with H₂ O (3×50ml), dried (Na₂ SO₄) andevaporated. The crude product was purified by distillation (1.2 g). δ(360 MHz, CDCl₃) 1.35-1.42 (2H, m, CH₂), 1.57-1.64 (2H, m, CH₂),2.00-2.40 (2H, m, CH₂), 2.36 (2H, t, J=9.0 Hz, CH₂), 3.15 (4H, m, t,J=7.0 Hz, 2 of CH₂), 3.33 (6H, s, 2 of OMe), 4.35 (1H, t, J=5.7 Hz, CH).

INTERMEDIATE 2

1-(4-Hydrazinophenyl)methyl-1,2,4-triazole

1. 1-(4-Nitrophenyl)methyl-1,2,4-triazole

4-Nitrobenzylbromide (21.6 g, 0.1 mol) was added to a rapidly stirredsuspension of 1,2,4-triazole sodium salt (9.1 g, 0.1 mmol) in anhydrousDMF (100 ml) and the mixture stirred at room temperature for 16 h. Ethylacetate (400 ml) was added followed by water (250 ml) and the layersseparated. The organic phase was washed with water (3×250 ml), dried(MgSO₄) and evaporated. The residue was chromategraphed on silica geleluting with ethyl acetate to give the title-product (10.6 g, 52%); m.p.98°-100° C. δ (360 MHz, CDCl₃) 5.47 (2H,s,CH₂), 7.40 (2H, d, J=9 Hz,Ar--H), 8.02 (1H,s,Ar--H), 8.18 (1H, s, Ar--H), 8.23 (2H, d, J=9 Hz,Ar--H).

2. 1-(4-Aminophenyl)methyl-1,2,4-triazole. Hydrochloride

A solution of 1-(4-nitrophenyl)methyl-1,2,4-triazole (10.0 g, 49 mmol)in ethanol (50 ml), ethyl acetate (50 ml), 5N HCl (10 ml) and water (10ml) was hydrogenated over 10% Pd/C(1.0 g) at 40 psi, in a Parrapparatus, until an uptake of 188 psi, had been observed (approx 10mins). The catalyst was removed by filtration through hyflo and thesolvent removed under vacuum. The residue was azeotroped with ethanol(×2) to give the title-amine hydrochloride (10.6 g, 100%). δ (360 MHz,D₂ O) 5.53 (2H, s, CH₂), 7.37-7.48 (4H, m, Ar--H), 8.12 (1H, s, Ar--H),8.66 (1H, s, Ar--H).

3. 1-(4-Hydrazinophenyl)methyl-1,2,4-triazole

A solution of sodium nitrite (3.28 g, 48 mmol) in water (20 ml) wasadded to a solution of the preceding amine hydrochloride (10.0 g, 48mmol), in concentrated HCl (40 ml), at such a rate that the temperaturedid not exceed -10° C. After addition was complete the solution wasstirred at 0° C. for 0.25 h and then added portionwise to a rapidlystirred solution of SnCl₂.2H₂ O (40 g) in concentrated HCl (40 ml). Thesolution was warmed to room temperature and basified with 20% aqueousNaOH solution. The solution was extracted with ethyl acetate (3×250 ml)and the combined extracts dried (MgSO₄) and filtered through hyflo. Thesolution was evaporated to dryness to give the desired hydrazine (5.0 g,56%) m.p. 109°-112° C. δ (360 MHz, D₆ --DMSO) 3.93 (2H, br s, NH₂), 5.20(2H, s, CH₂), 6.73 (2H, d, J=8 Hz, Ar--H), 7.08 (2H, d, J=8 Hz, Ar--H),7.92 (1H, s, Ar--H), 8.57 (1H, s, Ar--H).

N-2-[5-(1,2,4,-Triazol-1-ylmethyl)-1H-indol-3-yl)ethylazetid ine.Hydrogen Oxalate. Hemihvdrate.

A solution of 1-(4-hydrazinophenyl)methyl-1,2,4-triazole (0.92 g, 4.1mmol) and 4-(1-azetidinyl)butanal dimethylacetal (0.65 g, 3.8 mmol), in4% H₂ SO₄ (30 ml), was refluxed for 4.5 h. The solution was cooled toroom temperature, basified with K₂ CO₃ and extracted with EtOAc (4×100ml). The combined extracts were dried (Na₂ SO₄) and evaporated and theresidue chromatographed on silica-gel eluting with CH₂ Cl₂ /MeOH/NH₃(40:8:1) to give the title-indole. The hydrogen oxalate hemihydrate saltwas prepared (30 mg); m.p. 128°-129° C. Found: C, 57.28, H, 5.95; N,18.05. C₁₆ H₁₉ N₅.C₂ H₂ O₄.0.45 H₂ O requires C, 56.97; H, 5.82;N,18.45%). δ (360 MHz, D₂ O) 2.30-2.54 (2H, m, CH₂), 3.07 (2H, t, J=7.0Hz, CH₂), 3.52 (2H, t, J=7.0 Hz, CH₂), 3.94-4.13 (4H, m, 2 of CH₂), 5.51(2H, s, CH₂), 7.20 (1H, dd, J=1.5 and 8.4 Hz, Ar--H), 7.30 (1H, s,Ar--H), 7.51 (1H, d, J=8.4 Hz, Ar--H), 7.62 (1H, s, Ar--H), 8.05 (1H, s,Ar--H), 8.56 (1H, s, Ar--H).

EXAMPLE 2

N-2-[5-(1,2,4-Triazol-1-yl)-1H-indol-3-yl]ethylazetidine. Bisoxalate

INTERMEDIATE 3

4-(1,2,4-Triazol-1-yl)phenylhydrazine. Hydrochloride

1. 4-(1,2,4-Triazol-1-yl)nitrobenzene

1,2,4-Triazole sodium derivative (90%) (17.74 g, 0.18 mol) and1-fluoro-4-nitrobenzene (25 g, 0.18 mol), in DMF, (150 ml) was stirredat room temperature for 4 days. Water (300 ml) and ethyl acetate (500ml) were added and the mixture extracted. The organic layer wasseparated, washed with water (3×300 ml), dried (MgSO₄) and evaporated togive the desired product (24.8 g); δ (360 MHz, CDCl₃) 7.92 (2H, d, J=9.1Hz, Ar--H); 8.17 (1H, s, Ar--H); 8.40.(2H, d, J=9.1 Hz, Ar--H); 8.48(1H, s, Ar--H).

2. 4-(1,2,4-Triazol-1-yl)phenylhydrazine. Hydrochloride

Prepared from 4-(1,2,4-triazol-1yl)nitrobenzene using the proceduredescribed for the preparation of Intermediate 2. δ (360 MHz, CDCl₃) 3.66(2H, br s, NH₂), 5.36 (1H, br s, NH), 6.88-6.96 and 7.44-7.50 (both 2H,both m, At--H), 8.06 (1H, s, Ar--H), 8.42 (1H, s, Ar--H).

N-2-[5-(1,2,4-Triazol-1-yl)-1H-indol-3-yl]ethylazetidine. Bisoxalate

A solution of 4-(1,2,4-triazol-1-yl)phenylhydrazine hydrochloride (0.85g, 4.0 mmol) and 4-(1-azetidinyl)butanal dimethylacetal (0.63 g, 3.6mmol), in 4% H₂ SO₄ (30 ml), was heated at reflux for 5 h. The solutionwas cooled to room temperature, basified with saturated. K₂ CO₃ solutionand extracted with EtOAc (4×70 ml). The combined extracts were dried(Na₂ SO₄) and evaporated and the crude product chromategraphed onsilica-gel eluting with CH₂ Cl₂ /MeOH₃ (80:8:1) to give thetitle-product. The bisoxalate salt was prepared (0.16 g), m.p. 164-°165°C. Found: C, 48.26; H, 4.65, N, 14.09. C₁₅ H₁₇ N₅.2.55 (C₂ H₂ O₄)requires C, 48.58; H, 4.48; N, 14.09%. δ (360 MHz, D₂ O) 2.32-2.58 (2H,m, CH₂), 3.11 (2H, t, J=7.0 Hz, CH₂), 3.56 (2H, t, J=7.0 Hz, CH₂),4.00-4.17 (2H, m, CH₂), 7.40 (1H, s, Ar--H), 7.49 (1H, dd, J=2.0 and 8.7Hz, Ar--H), 7.64 (1H, d, J=8.7 Hz, Ar--H), 7.90 (1H, d, J=2.0 Hz,Ar--H), 8.47 (1H, s, Ar--H), 9.18 (1H, s, Ar--H).

EXAMPLE 3

N-Methyl-3-F5-(1,2,4-triazol-1-ylmethyl)-1H-indol,3-yl]methylazetidine.0.65 Oxalate

INTERMEDIATE 4

N-tert-Butyloxycarbonyl-3-(2-formyl)ethylazetidine

1. N-Diphenylmethylazetidin-3-ol

Amlnocliphenylmethane (100 g, 0.54 mol) was added to a solution ofepichlorohydrin (50 g, 0.54 mol) in DMSO (135 ml) and stirred at 25° C.for 3 days. The solution was then heated at 70° C. for 3 days beforecooling to room temperature, adding 10% NaOH solution, and extractingwith Et₂ O (2×800 ml). The combined extracts were washed with water(2×11), dried (Na₂ SO₄) and evaporated. The crude product waschromatographed on silica-gel eluting with CH₂ Cl₂ /MeOH (98:2) to givethe title-azetidinol (33.5 g). δ (360 MHz, CDCl₃) 2.30 (1H, br s, OH),2.87-2.91 (2H, m, 2 of CH of CH₂), 3.51-3.55 (2H, m, 2 of CH of CH₂),4.34 (1H, s, CH), 4.41-4.48 (1H, m, CH--OH), 7.13-7.39 (10H, m, Ar--H).

2. N-Diphenylmethylazetidin-3-one

Triethylamine (112.1 g, 1.11 mol) was added to a solution ofN-diphenylmethylazetidin-3-ol (26.6 g, 0.11 mol) in DMSO (300 ml). Thesolution was cooled to 10° C. and a solution of sulphurtrioxide-pyridine complex (112 g, 0.7 mol) in DMSO (500 ml) added,rapidly. Stirring was continued at 10° C. for 0.75 h and the mixturethen warmed to 25° C. and stirred for 1 h. The solution was poured intoice-water (21) and extracted with EtOAc (3×1l). The combined extractswere washed with water (500 ml) and brine (500 ml) and dried (Na₂ SO₄).The crude product was purified by chromatography through silica-geleluting with petroleum ether/EtOAc (2:1) to give the desired ketone(25.8 g), mp 74°-75° C. δ (360 MHz, CDCl₃) 4.00 (4H, s, 2 of CH₂), 4.59(1H, s, CH), 7.19-7.49 (10H, m, Ar--H).

3. Methyl (1-diphenylmethylazetidin-3-ylidene)acetate

Methyl diethylphosphonoacetate (11.0 g, 52.0 mmol) in THF (10 ml) wasadded dropwise to a stirred suspension of sodium hydride (2.1 g, 60%dispersion in oil, 52.5 mmol) in THF (40 ml), at 10° C. The mixture wasstirred for 0.6 h and a solution of the preceding azetidinone (11.3 g,48.0 mmol) in THF (50 ml) then added dropwise at 10° C. The mixture washeated at 50° C. for 3 h before removing the solvent under vacuum andredissolving the residue in CH₂ Cl₂ (200 ml). The solution was washedwith water (50 ml) and sodium bisulphite solution (2×50 ml) and dried(Na₂ SO₄). Chromatography of the residue obtained, after removing thesolvent, through silica-gel eluting with CH₂ Cl₂ /MeOH (98:2) gave thedesired ester (13.1 g), mp 83°-84° C.; δ (360 MHz, CDCl₃) 3.65 (3H, s,CO₂ Me), 3.88 (2H, m, 2 of CH of CH₂), 4.14-4.17 (2H, m, 2 of CH ofCH₂), 4.52 (1H, s, CH), 5.65-5.68 (1H, m, vinyl-H), 7.17-7.44 (10H, m,Ar--H).

4. N-Diphenylmethyl-3-carbomethoxymethylazetidine

A mixture of the compound from step 3 (21.0 g, 71.7 mmol), Pd(OH)₂ (3.0g, 20% on C), methanol (500 ml) and 2 N HCl (37 ml) was hydrogenated ona Parr shake apparatus for 2 h. The catalyst was removed by filtrationthrough celite and the solvents removed under vacuum. Saturated K₂ CO₃solution was added (50 ml) and extracted with CH₂ Cl₂ (2×250 ml). Thecombined extracts were washed with H₂ O (250 ml) and brine (100 ml),dried (Na₂ SO₄) and evaporated to give the title-product as a paleyellow oil (19.3 g). δ (360 MHz, CDCl₃) 2.58 (2H, d, J=7.3 Hz, CH₂),2.75-2.81 (3H, m, 2 of CH of CH₂ and CH), 3.35-3.38 (2H, m, 2 of CH ofCH₂), 3.62 (3H, s, CO₂ Me), 4.31 (1H, s, CH), 7.14-7.18, 7.23-7.27 and7.38-7.40 (total 10H, each m, Ar--H).

5. Ethyl-2-(1-Diphenylmethylazetidin-3-yl)alcohol

Diisobutylaluminium hydride (119 ml of a 1M solution in toluene, 0.119mol) was added dropwise to a stirred solution of the preceding ester(10.0 g, 33.9 mmol) in toluene (500 ml), at -35° C., over a 0.5 hperiod. The solution was warmed to 25° C., stirred for 2 h, and thencooled to 0° C. and quenched by addition of methanol (10 ml), 2N NaOH (5ml) and H₂ O (5 ml). The mixture was warmed to 25° C., filtered throughcelite and the solvent removed under vacuum. The residue waschromatographed on silica-gel eluting with ethyl acetate/hexane (1:1) togive the title-alcohol as a white crystalline solid, (4.1 g), mp 98°-99°C. Found: C, 80.73; H, 8.06; N, 5.38. C₁₈ H₂₁ NO requires C, 80.86; H,7.92; N, 5.24%). δ (360 MHz, CDCl₃) 1.64 (1H, br s, OH), 1.82 (2H, m,CH₂), 2.51-2.58 (1H, m, CH), 2.87-2.91 and 3.29-3.33 (both 2H, each m, 2of CH₂), 3.70 (2H, t, J=6.4 Hz, CH₂), 4.33 (1H, s, CH), 7.15-7.40 (10H,m, Ar--H).

6. Ethyl-2-(1-H-azetidin-3-yl)alcohol. Hydrochloride

Pd(OH)₂ (0.8 g, 20% on C) was added to a solution of the precedingalcohol (4.0 g, 15.0 mmol) in methanol (200 ml) and 1N HCl (10 ml), andthe mixture hydrogenated on a Parr shake apparatus for 24 h, at 55 psi.The mixture was filtered through celite and the solvent removed undervacuum. Diphenyl methane was removed by triturating the residue withether and decanting. The remaining product was dried under vacuum togive the desired product (2.0 g); δ (250 MHz, D₂ O) 1.86-1.94 (2H, m,CH₂), 2.98-3.16 (1H, m, CH), 3.60 (2H, t, J=6.4 Hz, CH₂), 3.86-3.96 and4.14-4.22 (both 2H, both m, 2 of CH₂).

7. Ethyl-2-(1-tert-butyloxycarbonylazetidin-3-yl )alcohol

A mixture of the product from step 6 (1.44 g, 10.5 mmol), triethylamine(3.21 ml, 22.9 mmol) and (BOG)₂ O (3.43 g, 15.7 mmol), in THF (90 ml)was stirred at 25° C. for 2 days. The solvent was removed under vacuum,water (70 ml) added and extracted with EtOAc (3×). The combined extractswere dried (MgSO₄), evaporated and the residue chromatographed onsilica-gel eluting with CH₂ Cl₂ /MeOH (95:5) to give the rifle-product(2.12 g). δ (250 MHz, CDCl₃) 1.42 (9H, s, 3 of CH₃), 1.56 (1H, s, OH),1.82-1.90 (2H, m, CH₂), 2.56-2.76 (1H, m, CH), 3.58-3.67 (4H, m, CH₂ and2 of CH of CH₂), 4.00-4.06 (2H, m, 2 of CH of CH₂).

8. Ethyl-2-(1-tert-butyloxycarbonylazetidin-3-yl )p-toluenesulphonate

A solution of p-toluenesulphonyl chloride (1.57 g, 8.2 mmol) in CH₂ Cl₂(20 ml) was added to a solution of the preceding alcohol (1.5 g, 7.46mmol) and triethylamine (8.2 mmol) in CH₂ Cl₂ (130 ml) at 0° C. Acatalytic amount of DMAP was added and the mixture warmed to +25° C. andstirred for 16 h. The residue remaining afar removal of solvent undervacuum was chromatographed on silica-gel eluting with CH₂ Cl₂ MeOH(99:1) to give the desired tosylato (1.7 g, 71%). δ (360 MHz, CDCl₃)1.42 (9 H, s, 3 of CH₃), 1.91-1.97 (2H, m, CH₂), 2.46 (3H, s, CH₃),2.53-2.61 (1H, m, CH), 3.51 (2H, dd, J=5.5 and 8.6 Hz, 2 of CH of CH₂),3.95 (2H, dd, J=8.5 and 8.6 Hz, 2 of CH of CH₂), 4.01 (2H, t, J=6.1 Hz,CH₂ --OTs), 7.36 (2H, d, J=8.1 Hz, Ar--H), 7.78 (2H, d, J=8.1 Hz,Ar--H).

9. Ethyl-2-(1-tert-butyloxycarbonylazetidin-3-yl)nitrile

NaCN (0.35 g, 7.1 mmol) was added to a solution of the precedingtosylate (1.7 g) in anhydrous DMSO (40 ml) and the mixture stirred at60° C. for 16 h. Saturated NH₄ Cl solution (30 ml) was added and themixture extracted with CH₂ Cl₂ (300 ml). The CH₂ Cl₂ extract was washedwith H₂ O (4×), dried (NaSO₄) and evaporated. The crude product waspurified by chromatography on silica-gel eluting with CH₂ Cl₂ /MeOH(98:2). The product was Obtained as a clear oil (0.92 g, 92%); δ (3601MHz, CDCl₃) 1.44 (9H, s, 3 of CH₃), 1.94-2.00 (2H, m, CH₂), 2.34 (2H, t,J=7.1 Hz, CH₂ CN), 2.61-2.69 (1H, m, CH), 3.59 (2H, dd, J=5.4 and 8.7Hz, 2 of CH of CH₂), 4.07 (2H, dd, J=8.4 and 8.7 Hz, 2 of CH of CH₂).

10. N-tert-Butyloxycarbonyl-3-(2-formyl)ethylazetidine

Diisobutylaluminium hydride (6.43 ml of a 1M solution in toluene, 6.4mmol) was added to a solution of the preceding nitrile (0.9 g, 4.3 mmol)in toluene (100 ml), at -60° C. The solution was warmed to +25° C. andstirred for 5 h before adding saturated NH₄ Cl solution (50 ml) andstirring for 16 h. The mixture was extracted with CH₂ Cl₂ (3 x), thecombined extracts dried (Na₂ SO₄) and the residue remaining, afterremoval of solvents under reduced pressure, chromatographed on silicagel, eluting with CH₂ Cl₂ /MeOH (98:2) to give the title-aldehyde (0.42g, 46%); δ (250 MHz, CDCl₃) 1.44 (9H, s, 3 of CH₃), 1.86-1.96 (2H, m,CH₂), 2.40-2.60 (3 H, m, CH and CH₂), 3.53 (2H, dd, J=5.4 and 8.7 Hz, 2of CH of CH₂), 4.00 (2H, dd, J=8.5 and 8.6 Hz, 2 of CH of CH₂).

N-H-3-[5-(1,2,4-Triazol-1-ylmethyl), 1H-indol-3-yl]methylazetidine

A mixture of the preceding aldehyde (0.4 g, 1.88 mmol) and1-(4-hydrazinophenyl)methyl-1,2,4-triazole hydrochloride (0.51 g, 2.26mmol) in 4% H₂ SO₄ was heated at reflux for 3 h. The solution was cooledto 0° C., basified (K₂ CO₃) and extracted with EtOAc (3×). The combinedextracts were dried (MgSO₄), evaporated, and the residue purified bychromatography on silica-gel eluting with CH₂ Cl₂ /MeOH/NH₃ (15:8:1).The product (0.16 g, 34%) was obtained as a colourless foam; δ (360 MHz,D₄ --MeOH) 2.94 (2H, d, J=7.6 Hz, CH₂), 3.04-3.16 (1H, m, CH), 3.46-3.54and 3.68-3.74 (both 2H, each m, 2 of CH₂), 5.36. (2H, s, CH₂), 7.02 (1H,s, Ar--H), 7.03 (1H, dd, J=1.5 and 8.4 Hz, Ar--H), 7.25 (1H, d, J=8.4Hz, Ar--H), 7.48 (1H, s, Ar--H), 7.87 (1H, s, Ar--H), 8.35 (1H, s,Ar--H).

N-Methyl-3-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylazetidine.0.65 Oxalate

To a cooled solution of the preceding 1H-azetidine (0.16 g, 0.60 mmol),NaCNBH₃ (45 mg, 0.72 mmol) and acetic acid (90.0 mg, 1.5 mmol), inmethanol (12 ml), was added a solution of formaldehyde (57.0 mg, 0.72mmol; 38% w/v) in methanol (13 ml), at such a rate as to keep thetemperature of the solution at 0° C. The mixture was stirred at 0° C.for 0.25 h and then warmed to room temperature and stirred for 1 h.Saturated K₂ CO₃ solution (15 ml) was added and the solvent removedunder vacuum. The aqueous was extracted with EtOAc (4×), the combinedextracts dried (MgSO₄) and the solvent evaporated. The crude product waschromatographed on silica-gel eluting with CH₂ Cl₂ EtOH/NH₃ (70:8:1) togive the title-product (0.12 g, 71%). The 0.65 oxalate salt wasprepared, mp 209°-210° C. Found: C, 61.31; H, 6.21; N, 20.23. CC₁₆ H₁₉N₅.0.65 (C₂ H₂ O₄) requires C, 61.14; H, 6.02; N, 20.61%); δ (360 MHz,D₂ O) 2.75 and 2.91 (total 3H, each s, N--CH₃), 3.04 and 3.09 (total 2H,each d, J=7.7 Hz, CH₂), 3.26-3.37 (1H, m, CH), 3.77 and 3.98 (total 2H,each dd, J=9.0 and 11.0 Hz, 2 of CH of CH₂), 4.14 and 4.32 (total 2H,each dd, J=6.3 and 11.0 Hz, 2 of CH of CH₂), 5.12 (2H, s, CH₂), 7.21(1H, d, J=8.4 Hz, Ar--H), 7.28 (1H, s, Ar--H), 7.51 (1H, dd, J=1.5 and8.4 Hz, Ar--H), 7.60 and 7.63 (total 1H, each s, Ar--H), 8.05 (1H, s,Ar--H), 8.54 (1H, s, Ar--H).

EXAMPLE 4

(±)N-Methyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H=indol-3-yl]methylpyrrolidine.Hydrogen Oxalate. 0.2 Hydrate

INTERMEDIATE 5

(±)-N-tert,Butyloxycarbonyl-2-(2-formyl)ethyl pyrrolidine

1. N-tert-Butyloxycarbonylpyrrole-2-carboxaldehyde

A mixture of pyrrole-2-carboxaldehyde (9.5 g, 0.1 mol), (BOC)₂ O (24.0g, 0.11 mol) and DMAP (0.25 g) in THF (150 ml) was stirred at roomtemperature for 16 h. The solvent was removed under vacuum and theresidue dissolved in CH₂ Cl₂ (200 ml) and washed with 10% citric add,water and brine. The organic layer was dried (Na₂ SO₄) and evaporated togive the desired product (20.9 g, 95%); δ (360 MHz, CDCl₃) 1.65 (9H, s,3 of CH₃), 6.28-6.30 (1H, m, Ar--H), 7.18-7.19 (1H, m, Ar--H), 7.43-7.45(1H, m, Ar--H). 2.trans-Methyl-2-N-tert-butyloxycarbonylpyrrol-2-yl)acrylate Prepared fromthe preceding aldehyde and methyl diethylphosphonoacetate as describedfor Intermediate 4 (step 3). The product (98%) was obtained as a paleyellow oil; δ (360 MHz, CDCl₃) 1.63 (9H, s, 3 of CH₃), 3.78 (3H, s,CH₃), 6.21 (1H, d, J=16.0 Hz, vinyl CH), 6.21-6.22 (1H, m, Ar--H),6.69-6.71 (1H, m, Ar--H), 7.38-7.39 (1H, m, Ar--H), 8.30 (1H, d, J=16.0Hz, vinyl CH).

3. (±)-Methyl-2-(N-tert-butyloxycarbonylpyrrolidin-2-yl) propionate

A solution of the product from step 2 (11.0 g, 43.8 mmol) in glacialAcOH (300 ml) was hydrogenated over PtO₂ (1.25 g) at 50 psi. Thecatalyst was removed by filtration through hyflo and the solvent removedunder vacuum. The crude product was chromategraphed on silica-geleluting with diethyl ether:petroleum ether (1:1) to give the title-ester(7.4 g, 67%); δ (360 MHz, CDCl₃) 1.46 (9H, s, 3 of CH₃), 1.53-2.07 (6H,m, 3 of CH₂), 2.24-2.40 (2H, m, CH₂), 3.25-3.46 (2H, m, CH₂), 3.67 (3H,s, CO₂ CH₃), 3.61-3.66 (1H, m, CH).

4. (±)-N-tert-Butyloxycarbonyl-2-(2-formyl) ethylpyrrolidine

To a cooled (-78° C.) solution of the preceding ester (4.0 g, 15.56mmol) in anhydrous toluene (75 ml) was added dropwise a solution ofdiisobutylaluminium hydride (18.7 ml of a 1M solution in toluene, 18.7mmol), at such a rate as to maintain the temperature below -75° C. Afterthe addition was complete the reaction was stirred at -78° C. for 4 hbefore adding MeOH (1 ml), H₂ O (1 ml) and sodium hydroxide (2N, 1 ml),successively, dropwise. The mixture was warmed to room temperature andthe precipitated salts removed by filtration through hyflo. The filtratewas dried (MgSO₄) and the solvent removed under vacuum. The residue waschromatographed on silica-gel eluting with ethyl acetate/petroleum ether(3:4) to give the title-compound (2.74 g, 78%) as a colourless oil; δ(360 MHz, CDCl₃) 1.46 (9H, s, 3 of CH₃), 1.58-1.99 (6H, m, 3 of CH₂),2.45 (2H, d t, J=1.2 and 7.5 Hz, CH₂ --CHO), 3.25-3.39 (2H, m, CH₂),3.78-3.88 (1H, m, CH), 9.76 (1H, t, J=1.2 Hz, CHO).

(±)-N-Methyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylpyrrolidine.Hydrogen Oxalate. 0.2 Hydrate.

Prepared from (±)N-tert-butyloxycarbonyl-2-(2-formyl) ethylpyrrolidineand 1-(4-hydrazinophenyl)methyl-1,2,4-triazole hydrochloride asdescribed for Example 3. The hydrogen oxalate salt was prepared, mp161°-162° C. (MeOH/ether). Found: C, 57.97; H, 5.82; N, 17.53. C₁₇ H₂₁N₅.C₂ H₂ O₄.0.2 H₂ O requires C, 57.94; H, 5.98; N, 17.53%); δ (360 MHz,D₂ O) 1.81-2.25 (4H, m, CH₂), 2.84 (3H, s, CH₃), 3.08-3.18, 3.29-3.35and 3.65-3.74 (2H, 1H, and 2H respectively, each m, 2 of CH₂ and CH),5.52 (2H, s, CH₂), 7.22 (1H, d, J=8.4 Hz, Ar--H), 7.36 (1H, s, Ar--H),7.53 (1H, d, J=8.4 Hz, Ar--H), 7.63 (1H, s, Ar--H), 8.08 (1H, s, Ar--H),8.59 (1H, s, Ar--H).

EXAMPLE 5

(2R )N-Methyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine. 1.3Benzoate. 0.9 Hydrate

INTERMEDIATE6

4'-(1,2,4-Triazol-4-yl)phenylhydrazine

1. 4'-Aminoacetanilide

A solution of 4-nitroacetanilide (5.0 g, 27.8 mmol) in EtOH/EtOAc (160ml, 1:1), H₂ O (15 ml) and 5N HCl (5.6 ml, 28.0 mmol) was hydrogenatedover 10% Pd-C (0.50 g) at 50 psi for 0.25 h. The catalyst was removed byfiltration through celite and the solvents removed under vacuum. Thefree base was generated by dissolving the product in H₂ O, basifyingwith 2N NaOH and extracting into EtOAc. The combined extracts were dried(MgSO₄) and evaporated to give the title-aniline (3.75 g, 90%). δ (250MHz, CDCl₃ /d₄ --MeOH) 2.10 (3H, s, CH₃), 6.68 (2H, d, J=8.8 Hz, Ar--H),7.27 (2H, d, J=8.8 Hz, Ar--H).

2. 4'-(1,2,4-Triazol-4-yl)acetanilide

A mixture of the preceding aniline (3.52 g, 23.4 mmol),N,N-dimethylformamide azine (3.33 g, 23.4 mmol; J. Chem. Soc., (C) 1967,1664) and p-toluenesulphonic acid monohydrate 25. (0.223 g, 1.17 mmol),in anhydrous toluene (100 ml), was heated at reflux for 17 h. The beigecoloured precipitate was filtered off and washed with toluene and CH₂Cl₂ and dried under vacuum to give the desired triazole (4.29 g, 91%); a(250 MHz, d₄ --MeOH/d₆ --DMSO) 2.14 (3H, s, CH₃), 7.60 (2H, d, J=8.8 Hz,Ar--H), 7.78 (2H, d, J=8.8 Hz, Ar--H), 8.96 (2 H, s, Ar--H).

3. 4'-(1,2,4-Triazol-4-yl)phenylaniline

A solution of the preceding acetanilide (4.91 g, 24.3 mmol) in 5N HCl(100 ml) was heated at 125° C. for 1.5 h. The mixture was cooled to 0°C., basified with concentrated aqueous NaOH solution and extracted withCH₂ Cl₂ (×5). The combined extracts were dried (MgSO₄) and evaporatedand the residue chromatographed on silica gel, eluting with CH₂ Cl₂/MeOH/NH₃ (80:8:1), to give the title-aniline (2.94 g, 76%); δ (250 MHz,CDCl₃) 3.80 (2H, s, NH₂), 6.71 (2H, d, J=8.8 Hz, Ar--H), 7.08 (2H, d,J=8.8 Hz, Ar--H), 8.36 (2H, s, Ar--H).

4. 4'-(1,2,4-Triazol-4-yl)phenylhydrazine

To a solution of the preceding aniline (1.60 g, 9.99 mmol) inconcentrated HCl/H₂ O (23 ml and 3 ml respectively) was added, at -21°C., a solution of NaNO₂ (0.69 g, 9.99 mmol) in H₂ O (8 ml), at such arate as to maintain the temperature below -10° C. The mixture wasstirred for 0.3 h and then filtered rapidly through a sinter, undervacuum. The filtrate was added to a cooled (-20° C.) solution ofSnCl₂.2H₂ O (9.02 g, 40.0 mmol) in concentrated HCl (17 ml). The mixturewas stirred at -20° C. for 0.25 h and then at room temperature for 1.25h. The resulting solid was filtered off, washed with Et₂ O and driedunder vacuum. The crude product was dissolved in H₂ O, basified withconcentrated aqueous NaOH and extracted with EtOAc (×5). The combinedextracts were dried (MgSO₄) and evaporated to afford the rifle-product(0.95 g, 54%); δ (250 MHz, CDCl₃ /d₄ --MeOH) 3.98 (3H, br s, NH andNH₂); 6.97 (2H, d, J=12.0 Hz, Ar--H); 7.25 (2H, d, J=12.0 Hz, Ar--H);8.48 (2H, s, Ar--H).

INTERMEDIATE 7

(2R)-N-tert-Butyloxycarbonyl-3-(pyrrolidin-2-yl)propanal

1. (2R)-N-tert-Butyloxycarbonylpyrrolidin-2-ylmethanol

A solution of di-tert-butyl dicarbonate (34.11 g, 156.3 mmol) in DCM(125 ml) was added dropwise to a stirred solution of D-prolinol (15.04g, 148.7 mmol) in CH₂ Cl₂ (125 ml) at 0° C. under nitrogen. The mixturewas stirred at 0° C. for 1 h and then at room temperature for 66 h.Evaporation of the solvent afforded the title-carbarnate (29.9 g, 100%);δ (360 MHz, CDCl₃) 1.47 (9H, s, ^(t) Bu), 1.60 (1H, br m, CH₂),1.72-1.89 (2H, m, OH₂), 2.00 (1H, m, CH₂), 3.31 (1H, m, CH₂), 3.46 (1H,m, OH₂), 3.55-3.66 (2H, m, CH₂), 3.95 (1H, br m, CH₂).

2. (2R)-N-tert-Butyloxycarbonylpyrrolidin-2-ylmethanol

DMSO (8.63 ml, 122 mmol) was added dropwise to a stirred solution ofoxalyl chloride (5.31 ml, 60.9 mmol) in CH₂ Cl₂ (350 ml) at -78° C.under nitrogen. The mixture was stirred at this temperature for 30 minsbefore adding a solution of the preceding alcohol (10.20 g, 50.68 mmol)in CH₂ Cl₂ (120 ml). After stirring at -78° C. for 95 mins,triethylamine (35.5 ml, 255 mmol) was added dropwise and the mixtureallowed to warm to room temperature. Water was added, the mixtureextracted with CH₂ Cl₂ and the combined extracts dried (MgSO₄) andevaporated. The residue was purified by flash chromatography on silicagel, eluting with 1:1 ethyl acetate/hexane, to afford the title-aldehyde(10.1 g, 100%); δ (360 MHz, CDCl₃) 1.38 and 1.41 (9H, 2×s, ^(t) Bu),1.79-2.06 (4H, m, CH₂), 3.39-3.48 (2H, m, CH₂), 3.98 and 4.14 (1H, 2×m,CH₂), 9.40 and 9.49 (1H, 2×s, CHO).

3.(2R)-trans-Methyl[N-tert-butyloxycarbonyl-3-(pyrrolidin-2-yl)]propenoate

Methyl diethylphosphonoacetate (3.71, 20.2 mmol) was added dropwise to astirred suspension of sodium hydride (0.81 g, 60% dispersion in oil,20.3 mmol) in THF (30 ml) at 4° C. under nitrogen. The mixture wasstirred at room temperature for 0.5 h, recooled to 2° C. and a solutionof the preceding aldehyde (4.03 g, 20.2 mmol) in THF (35 ml) addeddropwise, maintaining the temperature below 10° C. The mixture wasstirred at 7.5° C. for 2.5 h before evaporating the solvent in vacuo andredissolving the residue in CH₂ Cl₂. The solution was washed with water(×1), 20% w/v sodium bisulphite solution (×2) and water (×1), dried(MgSO₄) and evaporated. Flash chromatography on silica gel of theresidue, eluting with 40:60 ethyl acetate/hexane, afforded thetitle--ester (4.92 g, 95%); δ (360 MHz, CDCl₃) 1.42 (9H, br s, ^(t) Bu),1.78-1.88 (3H, m, CH₂), 2.08 (1H, m, CH₂), 3.44 (2H, br s, CH₂),3.74(3H, s, CO₂ Me), 4.37-4.50 (1H, m, CH), 5.83 (1H, d, J=15.2 Hz,vinyl CH), 6.83 (1H, m, vinyl CH).

4. (2R)-Methyl [N-tert-butyloxycarbonyl-3-(pyrrolidine2-yl) propanoate

A mixture of the preceding olefinic ester (4.34 g, 17.0 mmol) 10% Pd/C(0.43 g), methanol (30 ml) and water (10 ml) was hydrogenated on a Parrshake apparatus for 2 h. The catalyst was removed by filtration throughcelite and the solvents evaporated in vacuo. Flash chromatography of theresidue on silica gel, eluting with 30:70 ethyl acetate/hexane, affordedthe title--ester (4.21 g, 96%); [α]_(D) +36.5° (c 0.37, CH₂ Cl₂); δ (360MHz, CDCl₃) 1.46 (9H, s, ^(t) Bu), 1.54-2.02 (6H, m, CH₂), 2.33 (2H, t,J=7.8 Hz, m, CH₂), 3.29 (1H, m, CH₂), 3.39 (1H, m, CH₂), 3.67 (3H, s,CO₂ Me), 3.81 (1H, m, CH). 5.(2R)-N-tert-Butyloxycarbonyl-3-(pyrrolidin-2-yl)propanal

Prepared from the preceding ester using the procedure described for thepreparation of Intermediate 5 (step 4). δ (250 MHz, CDCl₃) 1.46 (9H, s,^(t) Bu), 1.58-1.99 (6H, m, CH₂), 2.45 (2H, dt, J=1.2 and 7.5 Hz, CH₂--CHO), 3.25-3.39 (2H, m, CH₂), 3.83 (1H, m, CH), 9.76 (1H, t, J=1.2 Hz,CHO).

(2R)-2-[5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine

A solution of 4'-(1,2,4-triazol-4-yl)phenylhydrazine dihydrochloride(1.12 g, 4.49 mmol) and(2R)-N-tert-butyloxycarbonyl-3-(pyrrolidin-2-yl)propanal (0.847 g, 3.73mmol) in 4% aqueous sulphuric acid (80 ml) was stirred at roomtemperature for 0.5 h and then heated at reflux for 25 h. After coolingto room temperature, n-butanol was added and the aqueous basified withsaturated aqueous potassium carbonate solution. The aqueous wasseparated and extracted further with n-butanol (×2). The combinedorganics were evaporated in vacuo and the residue flash chromategraphedon silica gel eluting with CH₂ CCl₂ /MeOH/NH₃ (20:8:1), to give thetitle--pyrrolidine (0.263 g, 26%); δ (360 MHz, d⁴ --MeOH) 1.47 (1H, m,CH₂), 1.68-1.94 (3H, m, CH₂), 2.61 (1H, m, CH₂), 2.92 (2H, d, J=6.8 Hz,CH₂), 3.01 (1H, m, CH₂), 3.42 (1H, pentet, J=7.4 Hz, CH), 7.19-7.22 (2H,m, Ar--H), 7.43 (1H, d, J=8.7 Hz, Ar--H), 7.71 (1H, d, J=1.8Hz, Ar--H),8.82 (2H, s, Ar--H).

(2R)-N-Methyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine.1.3 Benzoate. 0.9 Hydrate.

Prepared from the preceding pyrrolidine using the procedure describedfor Example 3. The benzoate salt was prepared; (Found: C, 66.13; H,6.34; N, 15.19. C₁₆ H₁₉ N₅.1.3(C₇ H₆ O₂). 0.9(H₂ O) requires C, 66.06;H, 6.32; N, 15.35%); δ (360 MHz, D₂ O) 1.86-2.09 (3H, m, CH₂), 2.27 (1H,m, CH₂), 2.86 (3H, s, CH₃), 3.13-3.21 (2H, m, CH₂), 3.38 (1H, dd, J=14.8and 6.0 Hz, CH₂), 3.68-3.76 (2H, m, CH₂), 7.34 (1H, dd, J=8.6 and 2.0Hz, Ar--H), 7.46-7.60 (5H, m, Ar--H), 7.65 (1H, d, J=9.0 Hz, Ar--H),7.76 (1H, d, J=2.0 Hz, Ar--H), 7.88-7.91 (2.5H, m, Ar--H), 8.82 (2H, s,Ar--H).

EXAMPLE 6

3-[trans-1-(Dimethylamino)cyclobutan-3-yl]-5-[(1,2,4-triazol-1-yl)methyl]-1H-indole and3-[cis-1-(Dimethylamino)cyclobutan-3-yl]-5-[(1,2,4-triazol-1-yl)methyl]-1H-indole. Hydrogen Oxalates.

1. cis/trans-1-Benzyloxy-3-(tert,butyloxycarbonyl amino)cyclobutane

To a stirred solution of cis/trans-3-benzyloxycyclobutane1-carboxylicadd (5.0 g, 24.24 mmol) (Coll. Czech. Chem. Commun., 1981, 47, 2440) inanhydrous 2-methyl-2-propanol (70 ml) was added anhydrous triethylamine(3.72 ml, 26.67 mmol) followed by diphenylphosphoryl azide (5.48 ml,25.45 mmol) and the resulting colourless clear solution was refluxed for19 hours under a nitrogen atmosphere. Solvents were removed under vacuumand the remaining liquid was dissolved in ethyl acetate (200 ml) and itwas washed with 1N hydrochloric add (1×50 ml), water (1×50 ml), 10%aqueous sodium bicarbonate (1×50 ml), brine (1×20 ml), then dried(MgSO₄) and concentrated. Flash chromatography of the residue (silicagel, hexane-ethyl acetate, 85:15 to 70:30) gave 3.30 g of the titlecompound (cis/trans 1:1) as a white solid; δ (250 MHz, CDCl₃) 7.38-7.25(5H, m, Ph--), 4.63 (1H, br s, --NH--), 4.40 (2H, s, PhCH₂ --),4.26-4.12 (1H, m, --CH--O), 3.75 (1H, qn, J=7.5 Hz, --CH--N), 2.78-2.64(1H, m, --CH₂ --), 2.50-2.36 (1H, m, --CH₂ --), 2.20-2.06 (1H, m, --CH₂--), 1.88-1.74 (1H, m, --CH₂ --), 1.44 (9H, s, t--Bu); m/z (CI) 276 (M⁻-1).

2. cis/trans-3-(tert-Butyloxycarbonyl amino)cyclobutan-1-ol

A solution of cis/trans-1-benzyloxy-3-(tertbutyloxycarbonylamino)cyclobutane (3.0 g) in absolute ethanol (40 ml) was hydrogenated at 20psi over 10% palladium on carbon (540 mg) for 2 hours. The catalyst wasremoved by filtration, washed with ethanol (2×20 ml) and the filtratewas concentrated under vacuum to give 2.05 g (100%) of the titlecompound (cis/trans, 1:1) as a waxy white solid; mp 64°-67° C.(hexane-ethyl acetate); δ (250 MHz, CDCl₃) 4.64 (2H, br s, --NH--),4.54-4.42 (1H, m, --CH--), 4.28-4.14 (1H, m, --CH--), 4.02 (1H, qn,J=7.3Hz, --CH--), 3.74-3.56 (1H, m, --CH--), 2.84-2.70 (2H, m, --CH₂--), 2.40-2.14 (4H, m, --CH₂), 1.88-1.70 (4H, m, --CH₂ -- and --OH),1.43 (18H, s, t--Bu); m/z (CI) 187 (M⁻). (Found: C, 58.02; H, 9.02; N,7.25. C₉ H₁₇ NO₃ requires: C, 57.73; H, 9.15; N, 7.48%.)

3. 3-(tert-Butyloxycarbonylamino)cyclobutan-1-one

To a stirred solution of the product from the previous step (500 mg,2.67 mmol) and N-methylmorpholine N-oxide monohydrate (541 mg, 4.0 mmol)in anhydrous dichloromethane (27 ml) were added 4 Å molecular sieves(500 mg) and the mixture was stirred for 15 minutes prior to theaddition of tetrapropylammonium perruthenate (47 mg, 0.13 mmol). Afterbeing stirred for 1.5 hours under a nitrogen atmosphere, the mixture wasdiluted with dichloromethane (100 ml) and it was washed with 10% aqueoussodium sulphite (1×25 ml), brine (1×25 ml) and saturated aqueous copper(II) sulphate (1×25 ml). The organic solution was filtered through aplug of flash silica gel (40 g) and this was washed with ethyl acetate(3×20 ml). The filtrate was concentrated under vacuum and the remainingresidue was purified by flash chromatography (silica gel, hexane-ethylacetate, 60:40) to give 410 mg (83%) of the title compound as a whitesolid; mp 75°-78° C.; δ (360 MHz, CDCl₃) 4.90 (1H, br s, --NH--),4.32-4.22 (1H, m, --CH--), 3.46-3.34 (2H, m, --CH₂ --), 3.08-2.98 (2H,m, --CH₂ --), 1.46 (9H, s, t--Bu); m/z (CI) 186 (M⁺ +1). (Found: C,58.31; H, 7.96; N, 7.59. C₉ H₁₅ NO₃ requires: C, 58.36; H, 8.16; N,7.56%.)

4. 1-(tert-Butyloxycarbonylamino)-3-(carbomethoxymethylene)cyclobutane

To a cooled (-70° C.) and stirred solution of trimethyl phosphonoacetate(1.5 g) in anhydrous tetrahydrofuran (40 ml) was added potassiumbis(trimethylsilyl)amide (0.5M in toluene; 15.07 ml) at such a rate asto maintain the internal temperature below -62° C. (ca 8 min). After 15minutes of stirring at -70° C., a solution of3-(tert-butyloxycarbonylamino)cyclobutan-1-one (1.27 g) in anhydroustetrahydrofuran (10 ml) was added over 9 minutes, under a nitrogenatmosphere. The mixture was then allowed to warm to room temperature andit was stirred for 1 hour before it was quenched with saturated aqueousammonium chloride (40 ml). Products were extracted with ethyl acetate(2×50 ml) and the combined organic solutions were washed with brine(1×40 ml), dried (MgSO₄) and concentrated. Flash chromatography of theresidue (silica gel, hexane-ethyl acetate, 75:25) gave 1.61 g (97%) thetitle compound as a white solid; mp 79°-82° C. δ (250 MHz, CDCl₃) 5.70(1H, m, --CH--), 4.81 (1H, br s, --NH--), 4.32-4.13 (1H, m, --CH--),3.69 (3H, s, --OMe), 3.64-3.50 (1H, m, --CH₂ --), 3.26-3.10 (1H, m,--CH₂ --), 3.00-2.86 (1H, m, --CH₂ --), 2.80-2.68 (1H, m, --CH₂ --),1.45 (9H, s, t--Bu); m/z (CI) 240 (M⁻ -1). (Found: C, 60.28; H, 7.87; N,5.76. C₁₂ H₁₉ NO₄ ×0.03 C₆ H₁₄ requires: C, 59.99; H, 8.02; N, 5.75%.)

5.cis/trans-1-(tert-Butyloxycarbonylamino)-3-(carbomethoxymethyl)cyclobutane

A solution of the product from the previous step (1.5 g) in absoluteethanol (40 ml) was hydrogenated at atmospheric pressure over 10%palladium on carbon (200 mg) for 2 hours. The catalyst was filtered off,washed with ethanol (1×25 ml) and the solvent was removed under vacuumto give the title compound (1.48 g, 98%) as a white solid (cis/trans ca2:1); mp 69°-73° C.; m/z (CI) 243 (M⁻).

6. [cis/trans-1-(tert-Butyloxycarbonylamino)cyclobutan-3-yl]acetaldehyde

To a cooled (-79° C.) and stirred solution of the product from theprevious step (1.46 g, 6.0 mmol) in anhydrous toluene (90 ml) was addeddropwise via cannula diisobutylaluminium hydride (1M in toluene; 15 ml)at such a rate as to maintain the internal temperature below -78° C. (ca18 minutes). The resulting mixture was stirred at -80° C. for 1 hourbefore anhydrous methanol (4.9 ml) was added dropwise at such a rate asto maintain the temperature below -78° C. Aqueous citric acid (10%; 75ml) was added and the mixture was allowed to warm to room temperature.Products were extracted with ethyl acetate (3×100 ml), washed with brine(1×70 ml), dried (MgSO₄) and concentrated. Flash chromatography of theresidue (silica gel, hexane-ethyl acetate, 60:40) gave 1.22 g (95%)ofthe title aldehyde as a thick colourless oil which solidified onstanding; δ (250 MHz, CDCl₃) 11.25 (1H, s, --CHO); m/z (CI) 212 (M⁻ -1).

7.3-[trans-1-(Dimethylamino)cyclobutan-3-yl]-5-[(1,2,4-triazol-1-yl)methyl]-1H-indoleand 3-[cis-1-(Dimethylamino)cyclobutan-3-yl]-5-[(1,2,4triazol-1-yl)methyl]-1H-indole. Hydrogenoxalates.

To a solution of the aldehyde from the previous step (1.06 g, 4.97 mmol)in absolute ethanol (2.5 ml) was added 4% aqueous sulfuric acid (5 ml)followed by 1-(4-hydrazinophenyl) methyl-1,2,4-triazole dihydrochloride(1.3 g, 4.97 mmol). After being stirred for 1 minute, 4% aqueoussulfuric acid (40 ml) was slowly added over 5 minutes and the reactionmixture was refluxed for 1 hour and 20 minutes. After being cooled toroom temperature, methanol (100 ml) was added and the mixture wasbasified with saturated aqueous potassium carbonate (20 ml). Theprecipitated solids were filtered off, washed with methanol (2×30 ml)and solvents were removed under vacuum. The remaining residue wastriturated with hot ethanol (50 ml) and the undissolved solid wasremoved by filtration and washed with ethanol (2×30ml). The resultingclear filtrate was concentrated under vacuum and the residue waspurified by flash chromatography (silica gel,dichloromethane-methanol-ammonia, 85:15:1.5) to give 545 mg (41%) of3-(1-aminocyclobutan-3-yl)-5-[(1,2,4-triazol-1-yl)methyl]-1H-indole as amixture of cis and trans isomers.

To a cooled (0° C.) and stirred solution ofcis/trans-3-(1-aminocyclobutan-3-yl)-5-[(1,2,4-triazol-1-yl)methyl]-1H-indole (270 mg, 1.0 mmol) in anhydrous methanol (20 ml) were addedsodium cyanoborohydride (127 mg, 2.0 mmol), glacial acetic acid (289 μl,5.0 mmol) and a solution of formaldehyde (38% w/v aqueous solution; 200μl) in absolute methanol (3 ml). The reaction mixture was then allowedto warm to room temperature and it was stirred for 1.5 hours beforesaturated aqueous potassium carbonate (10 ml) was added and the methanolwas removed under vacuum. The aqueous residue was extracted with ethylacetate (3×50 ml) and the combined organic solutions were washed withbrine (2×15 ml), dried (Na₂ SO₄) and concentrated. The remaining residuewas purified by preparative TLC (silica gel,dichloromethane-methanol-ammonia, 90:10:1) to give 102 mg (34%) of3-[cis-1-(dimethylamino)cyclobutan-3-yl]-5-[(1,2,4-triazol-1-yl)methyl]-1H-indole(less polar isomer) and 132 mg (44%) of 3-[trans-1-(dimethylamino)cyclobutan-3-yl]-5-[(1,2,4-triazol-1-yl) methyl]-1H-indole (morepolar isomer). The hydrogen oxalate salts were prepared and showed:

Cis-ISOMER: mp 223°-226° C. (ethanol-methanol); δ (250 MHz, D₂ O) 8.54(1H, s, Ar--H), 8.05 (1H, s, Ar--H), 7.63 (1H, br d, Ar--H), 7.50 (1H,d, J=8.4 Hz, Ar--H), 7.28 (1H, s, Ar--H), 7.20 (1H, dd, J=8.4 and 1.8Hz, Ar--H), 5.50 (2H, s, Ar--CH₂), 3.82-3.68 (1H, m, --CH--), 3.54-3.36(1H, m, --CH--), 2.96-2.80 (8H, m and s, --CH₂ -- and --NMe₂), 2.36-2.20(2H, m, --CH₂ --). (Found: C, 59.20; H, 6.37; N, 17.78. C₁₇ H₂₁ N₅ ×1.0C₂ H₂ O₄ requires: C, 59.21; H, 6.02; N, 18.17%.)

Trans-ISOMER: mp 137°-139° C. (ethanol); δ (250 MHz, D₂ O) 8.54 (1H, s,Ar--H), 8.05 (1H, s, Ar--H), 7.54 (1H, br s, Ar--H), 7.51 (1H, d, J=8.5Hz, Ar--H), 7.35 (1H, s, Ar--H), 7.22 (1H, dd, J═8.5 and 1.8 Hz, Ar--H),5.49 (2H, s, Ar--CH₂ --), 3.94-3.66 (2H, m, --CH--), 2.84-2.66 (8H, sand m, --NMe₂ and --CH₂ --), 2.62-2.48 (2H, m, --CH₂ --); m/z (CI) 296(M⁺ +1). (Found: C, 59.33; H, 6.28; N, 17.82. C₁₇ H₂₁ N₅ ×1.0 C₂ H₂ O₄requires: C, 59.21; H, 6.02; N, 18.17%.)

An X-ray crystal structure was obtained for the cis-ISOMER hydrogenoxalate which confirmed the initial assignment based on experimentscarded out on the free bases.

EXAMPLE 7

N-2-[5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl]ethylazetidine. Oxalate. 1.6Hydrate

A mixture of Intermediate 1 (0.75 g, 4.3 mmol) and 4%(1,2,4-triazol-4-yl)phenylhydrazine (0.75 g, 4.3 mmol), in 4% H₂ SO₄ (50ml) was heated at reflux for 22 h. The mixture was cooled to roomtemperature, basified with K₂ CO₃ and extracted with EtOAc (3×100 ml).The resultant crude product was chromatographed on silica gel elutingwith CH₂ Cl₂ /MeOH/NH₃ (40:8:1) to give the title-product (0.12 g). Theoxalate hydrate salt was prepared; mp 218°-220° C. (Found: C, 52.86; H,5.63; N, 17.98. C₁₇ H₁₅ N₅.C₂ H₂ O₄ 1.6H₂ O requires C, 52.87; H, 5.79;N, 18.13%.) δ (360 MHz, D₂ O) 2.36-2.63 (2H, m, CH₂), 3.06 (2H, t, J=7.0Hz, CH₂), 3.52 (2H, t, J=7.0 Hz, CH₂), 4.01-4.22 (4H, m, 2 of CH₂), 7.21(1H, dd, J=2.0 and 8.6 Hz, Ar--H), 7.39 (1H, s, Ar--H), 7.56 (1H, d,J=8.6 Hz, Ar--H), 7.62 (1H, d, J=2.0 Hz, Ar--H), 8.91 (2H, s, Ar--H).

EXAMPLE 8

N-2-[5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl]ethylpyrrolidine. Oxalate

INTERMEDIATE 8

4-(1-Pyrrolidinyl)butanal dimethylacetal

A solution of 4-chlorobutanal diethylacetal (10 g, 55.40 mmol) inpyrrolidine (40 ml) was heated at reflux for 16 h. The solvent wasremoved under vacuum, 2N NaOH (50 ml) added and the mixture extractedwith CH₂ Cl₂ (100ml). The extract was dried and evaporated and theresidue distilled (74° C., 1 mmHg) to give the title-product (8.8 g,74%). δ (250 MHz, D₆ --DMSO) 1.10 (6H, t, J=7.5 Hz, 2 of CH₃), 1.34-1.70(8H, m, 4 of CH₂), 2.28-2.40 (6H, m, 3 of CH₂), 3.26-3.60 (4H, m, 2 ofCH₂ O), 4.46 (1H, t, J=5.5Hz, CHO).

N-2-[5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl]ethylpyrrolidine. Oxalate

The title-compound was prepared from Intermediates 6 and 8 using theprocedure described for Example 7. The oxalate salt was prepared; mp244°-245° C.; (Found: C, 62.25; H, 6.06; N, 21.33. C₁₆ H₁₉ N₅.0.5(C₂ H₂O₄)0.1H₂ O requires C, 62.22; H, 6.20; N, 21.34%); δ (250 MHz, D₂ O)1.78-1.86 (4H, m, 2 of CH₂), 2.86-3.08 (8H, m, 4 of CH₂), 7.32 (1H, dd,J=2.0 and 8.6 Hz, Ar--H), 7.36 (1H, d, J=2.0 Hz, Ar--H), 7.50 (1H, d,J=8.6 Hz, Ar--H), 7.85 (1H, d, J=2.0 Hz, Ar--H), 9.02 (2H, s, Ar--H),11.18 (1H, s, indole NH).

EXAMPLE 9 Tablet Preparation

Tablets containing 1.0, 2.0, 25.0, 26.0, 50.0 and 100.0 mg, respectivelyof the following compounds are prepared as illustrated below:

N-2-[5-(1,2,4-Triazol-1-ylmethyl)-1H-indol-3-yl]ethyl azetidine.Hydrogen Oxalate.

N-2-[5-(1,2,4-Triazol-1-yl)-1H-indol-3-yl]ethylazetidine. Bisoxalate.

N-Methyl-3-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylazetidine.0.65 Oxalate.

(±)N-Methyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylpyrrolidine.Hydrogen Oxalate. 0.2 Hydrate.

(2R)N-Methyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine.1.3 Benzoate. 0.9 Hydrate.

3-[trans-1-(Dimethylamino)cyclobutan-3-yl]-5-[(1,2,4-triazol-1-yl)methyl]-1H-indole and3-[cis-1-(Dimethylamino)cyclobutan-3-yl]-5-[(1,2,4-triazol-1-yl)methyl]-1H-indole. Hydrogen Oxalates.

N-2-[5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl]ethylazetidine. Oxalate. 1.6Hydrate

N-2-[5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl]ethylpyrrolidine. Oxalate.

    ______________________________________                                        TABLE FOR DOSES CONTAINING FROM                                               1-25 MG OF THE ACTIVE COMPOUND                                                               Amount-mg                                                      Active Compound  1.0       2.0    25.0                                        ______________________________________                                        Microcrystalline cellulose                                                                     49.25     48.75  37.25                                       Modified food corn starch                                                                      49.25     48.75  37.25                                       Magnesium stearate                                                                             0.50      0.50   0.50                                        ______________________________________                                    

    ______________________________________                                        TABLE FOR DOSES CONTAINING FROM                                               26-100 MG OF THE ACTIVE COMPOUND                                              Active Compound  26.0      50.0   100.0                                       ______________________________________                                        Microcrystalline cellulose                                                                     52.0      100.0  200.0                                       Modified food corn starch                                                                      2.21      4.25   8.5                                         Magnesium stearate                                                                             0.39      0.75   1.5                                         ______________________________________                                    

All of the active compound, cellulose, and a portion of the corn starchare mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg,50.0 mg and 100 mg of the active ingredient per tablet.

We claim:
 1. A compound of formula I, or a pharmaceutically acceptablesalt or prodrug thereof: ##STR40## wherein the broken circle representstwo non-adjacent double bonds in any position in the five-memberedring;two, three or four of V, W, X, Y and Z represent nitrogen and theremainder represent carbon provided that, when two of V, W, X, Y and Zrepresent nitrogen and the remainder represent carbon, then the saidnitrogen atoms are in non-adjacent positions within the five-memberedring; A¹ represents hydrogen, hydrocarbon selected from the groupconsisting of: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkyl (C₁₋₆) alkyl, aryl and aryl. (C₁₋₆) alkyl, where aryl isphenyl; a heterocyclic group selected from the group consisting of: C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkyl (C₁₋₆) alkyl, heteroaryl andheteroaryl (C₁₋₆) alkyl wherein heterocycloalkyl is selected from:azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl; andheteroaryl is selected from: pyridyl, quinolyl, isoquinolyl,pyridazinyl, .pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl andthiadiazolyl; halogen, cyano, trifluoromethyl, --OR^(x), --SR^(x),--NR^(x) R^(y), --NR^(x) COR^(y), --NR^(x) CO₂ R^(y), --NR^(x) SO₂R^(y), or --NR^(z) CTNR^(x) R^(y) ; A² represents a non-bonded electronpair when four of V, W, X, Y and Z represent nitrogen and the otherrepresents carbon; or, when two or three of V, W, X, Y and Z representnitrogen and the remainder represent carbon, A² represents hydrogen,hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl,--OR^(x), --SR^(x), --NR^(x) R^(y), --NR^(x) COR^(y), --NR^(x) CO₂R^(y), --NR^(x) SO₂ R^(y), or --NR^(z) CTNR^(x) R^(y) ; wherein A¹ andA², where A² is not a non-bonded electron pair can be optionallysubstituted with trifluoromethyl, C₁₋₆ alkoxy, C₂₋₆ alkoxycarbonyl, C₂₋₆alkylcarbonyl, C₁₋₆ alkylsulphonyl, arylsulphonyl, amino, mono- ordi(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, arylcarbonylamino, C₂₋₆alkoxycarbonylamino, C₁₋₆ alkylsulphonylamino, arylsulphonylamino, C₁₋₆alkylsulphonylaminomethyl, aminocarbonylamino, mono- or di(C₁₋₆)alkylamino-carbonylamino, mono- or diarylaminocarbonylamino,pyrrolidylcarbonylamino, aminocarbonyl, mono- ordi(C₁₋₆)alkylaminocarbonyl, C₁₋₆ alkylaminosulphonyl,aminosulphonylmethyl, and mono- or di(C₁₋₆) alkylamino-sulphonylmethyl;E represents a bond or a straight or branched alkylene chain containingfrom 1 to 4 carbon atoms; F represents a group of formula ##STR41## Urepresents nitrogen or C--R² ; B represents oxygen, sulphur or N--R³ ;R¹ represents a group of formula (i), (ii) or (iii): ##STR42## in whichM represents the residue of an azetidine, pyrrolidine or piperidine ringwherein formula (i) represents azetidin-1-ylethyl, pyrrolidin-1-ylethylor piperidin-1-ylethyl; p is zero or 1 and q is an integer from 1 to 4,provided that the sum of p+q is 2, 3 or 4; R², R³, R⁴, R⁵ and R⁶independently represent hydrogen or C₁₋₆ alkyl; R^(x) and R^(y)independently represent hydrogen, hydrocarbon or a heterocyclic group,both as defined above, or R^(x) and R^(y) together represent a C₂₋₆alkylene group; R^(z) represents hydrogen, hydrocarbon or a heterocyclicgroup, both as defined above; T represents oxygen, sulphur or a group offormula ═N--G; and G represents hydrocarbon, a heterocyclic group, bothas defined above, or an electron-withdrawing group.
 2. A compound offormula I as claimed in claim 1, or a pharmaceutically acceptable saltor prodrug thereof, wherein R¹ represents a group of formula (i) or (ii)as defined in claim
 1. 3. A compound as claimed in claim 1 representedby formula II, or a pharmaceutically acceptable salt or prodrug thereof:##STR43## wherein Y¹ represents nitrogen or A¹² --C;Z¹ representsnitrogen or CH; n is zero, 1, 2 or 3; B¹ represents oxygen, sulphur orN--R¹³ ; A¹¹ and A¹² independently represent C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, aryl, aryl (C₁₋₆) alkyl, C₃₋₇heterocycloalkyl, heteroaryl, heteroaryl (C₁₋₆) alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino or di (C₁₋₆) alkylamino, any of which groupsmay be optionally substituted as defined in claim 1 for A¹ and A² ; orhydrogen, halogen, cyano, trifluoromethyl or amino; R¹¹ represents agroup of formula (iv), (v), (vi), (vii) or (viii): ##STR44## and R¹²,R¹³, R¹⁴, R¹⁵ and R¹⁶ independently represent hydrogen or C₁₋₆ alkyl. 4.A compound as claimed in claim 3 wherein A¹¹ and A¹² both representhydrogen.
 5. A compound as claimed in claim 3 wherein R¹² and R¹³ bothrepresent hydrogen.
 6. A compound as claimed in claim 3 wherein R¹⁴, R¹⁵and R¹⁶ each represents methyl.
 7. A compound as claimed in claim 1selectedfrom:N-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylazetidine;N-2-[5-(1,2,4-triazol-1-yl)-1H-indol-3-yl]ethylazetidine;N-methyl-3-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylazetidine;N-methyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]methylpyrrolidine;(2R)-N-methyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine;3-[cis-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-1H-indole;3-[trans-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-1H-indole;N-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethylazetidine;N-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethylpyrrolidine;or apharmaceutically acceptable salt or prodrug thereof.
 8. A pharmaceuticalcomposition comprising a compound of formula I as defined in claim 1 ora pharmaceutically acceptable salt thereof or a prodrug thereof inassociation with a pharmaceutically acceptable carrier.
 9. A method forthe treatment of migraine and associated conditions selected from thegroup consisting of: cluster headache, chronic paroxysmal hemicrania,headache associated with vascular disorders, tension headache andpediatric migraine for which a selective agonist of 5-HT₁ -likereceptors is indicated, which method comprises administering to apatient in need of such treatment an effective amount of a compound offormula I as defined in claim 1, or a pharmaceutically acceptable saltthereof or a prodrug thereof.